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CN1183118A - Thermitase variants having decreased adsorption and increased hydrolysis - Google Patents

Thermitase variants having decreased adsorption and increased hydrolysis Download PDF

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Publication number
CN1183118A
CN1183118A CN96193608A CN96193608A CN1183118A CN 1183118 A CN1183118 A CN 1183118A CN 96193608 A CN96193608 A CN 96193608A CN 96193608 A CN96193608 A CN 96193608A CN 1183118 A CN1183118 A CN 1183118A
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amino acid
asn
substitution occurs
asp
glu
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P·F·布罗德三世
B·L·巴尔内特
D·N·鲁宾
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Procter and Gamble Co
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Procter and Gamble Co
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    • C—CHEMISTRY; METALLURGY
    • C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
    • C11D—DETERGENT COMPOSITIONS; USE OF SINGLE SUBSTANCES AS DETERGENTS; SOAP OR SOAP-MAKING; RESIN SOAPS; RECOVERY OF GLYCEROL
    • C11D3/00—Other compounding ingredients of detergent compositions covered in group C11D1/00
    • C11D3/16—Organic compounds
    • C11D3/38—Products with no well-defined composition, e.g. natural products
    • C11D3/386—Preparations containing enzymes, e.g. protease or amylase
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof
    • A61K8/66—Enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q11/00—Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
    • C—CHEMISTRY; METALLURGY
    • C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
    • C11D—DETERGENT COMPOSITIONS; USE OF SINGLE SUBSTANCES AS DETERGENTS; SOAP OR SOAP-MAKING; RESIN SOAPS; RECOVERY OF GLYCEROL
    • C11D3/00—Other compounding ingredients of detergent compositions covered in group C11D1/00
    • C11D3/0005—Other compounding ingredients characterised by their effect
    • C11D3/0078—Compositions for cleaning contact lenses, spectacles or lenses
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
    • C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
    • C12N9/52—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from bacteria or Archaea

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Abstract

本发明涉及具有野生型热酶氨基酸序列的修饰氨基酸序列的热酶(thermitase)变异体,野生型氨基酸序列包括第一环区域、第二环区域、第三环区域、第四环区域、第五环区域和第六环区域;其中,修饰的氨基酸序列在一个或多个环区域中的特定标记的位点上含有与野生型热酶不同的氨基酸(即取代),从而与野生型热酶相比,热酶变异体具有对不溶解底物降低的吸附作用和增加的水解作用。本发明还涉及编码这种热酶变异体的DNA序列。本发明还涉及含有这种热酶变异体的用于洗涤各种表面的组合物。The present invention relates to a thermozyme (thermitase) variant having a modified amino acid sequence of a wild-type thermozyme amino acid sequence, the wild-type amino acid sequence comprising a first loop region, a second loop region, a third loop region, a fourth loop region, a fifth loop region loop region and the sixth loop region; wherein the modified amino acid sequence contains amino acids (i.e. substitutions) different from the wild-type thermozyme at specific labeled positions in one or more of the loop regions, thereby being comparable to the wild-type thermozyme Compared to that, the thermozyme variants had reduced adsorption and increased hydrolysis of insoluble substrates. The present invention also relates to DNA sequences encoding such thermozyme variants. The present invention also relates to compositions for cleaning various surfaces containing such thermozyme variants.

Description

Hot enzyme variant body with hydrolytic action of the adsorption of reduction and increase
Technical field
The present invention relates to the dna sequence dna of new enzyme variant body that is used for various cleaning composition and coding this kind of enzyme varient.
Background of invention
Enzyme has constituted the protein of the natural generation of maximum kind.The different types of chemical reaction of the common catalysis of each fermentoid (accelerated reaction and be not consumed).Being called that a kind of enzyme of proteolytic enzyme is known can hydrolysis (decomposition compound becomes two or more simpler compounds, accepts the H and the OH part of water molecules in the both sides of the chemical bond of fracture) other protein.Natural generation added this ability of promptly having utilized protein hydrolysate in the detergent for washing clothes preparation with protein engineering proteolytic enzyme as additive.Many dirts on clothes are proteinic, and the proteolytic enzyme of wide spectrum can significantly improve removing of this dirt.
Unfortunately, these protein are natural at it, and the efficacy levels in the environment of bacterium can not be transferred to non-natural relatively wash environment usually.Especially property of protease, for example thermostability, pH stability, oxidative stability and substrate characteristic may not reach best for the application outside the natural surroundings of enzyme.
The aminoacid sequence of proteolytic enzyme has determined the feature of proteolytic enzyme.According to the site that changes in the aminoacid sequence, character and/or amplitude, the characteristic that the aminoacid sequence of change proteolytic enzyme can change enzyme is to the degree that has nothing in common with each other, even deactivatable enzyme.People have made many trials changing the wild-type amino acid sequence of proteolytic enzyme, improving their character, thereby increase the efficient of proteolytic enzyme in wash environment.These trials comprise the change aminoacid sequence so that improve thermostability and improve oxidative stability under significantly different condition.
Although described various trials in the prior art, people still constantly need be used to wash the new effectively varient of the proteolytic enzyme on various surfaces.
Goal of the invention
Hot enzyme (Thermitase) varient of the hydrolytic action that the object of the present invention is to provide compares with wild-type enzyme has improvement.
Another object of the present invention is to provide the cleaning composition that contains these subtilisin variants.
Summary of the invention
The present invention relates to have the hot enzyme variant body of the modified amino acid sequence of the hot enzyme amino acid sequence of wild-type, the wild-type amino acid sequence comprises the first ring zone, the second ring zone, the 3rd ring zone, zone, Fourth Ring and zone, five rings; Wherein, contain the amino acid different (promptly replacing) on the site of the specific markers of aminoacid sequence in one or more rings zone of modifying with the hot enzyme of wild-type, compare with the hot enzyme of wild-type, hot enzyme variant body has the adsorption of not dissolving the substrate reduction and the hydrolytic action of increase.The invention still further relates to the dna sequence dna of this hot enzyme variant body of coding.The invention still further relates to the composition that is used to wash various surfaces that contains this hot enzyme variant body.
The hot enzyme variant body of detailed Description Of The Invention I.
The present invention relates to the subtilisin class, especially hot enzyme, the sudden change of their various nucleotide sequences by codase, thus change the aminoacid sequence of enzyme and modified.Modification subtilisin of the present invention (hereinafter referred to as " hot enzyme variant body ") is compared with the hot enzyme of wild-type, has not dissolving the adsorption that substrate reduces and the hydrolytic action of increase.The invention still further relates to the dna sequence dna of this hot enzyme variant body of coding.
Subtilisin of the present invention belongs to and is called protease.Proteolytic enzyme is the catalyzer of fracture peptide bond.One type proteolytic enzyme is serine protease.Serine is characterised in that and has essential serine residue on avtive spot.
Along with the increase enzyme of enzyme concn has been made abundant report to the phenomenon of the hydrolysis rate increase of solubilized substrate.Thereby, for the substrate of surface bonding, situation about in many washings are used, running into for example, hydrolysis rate increases seemingly possible along with the increase of surface concn, and this is by statement of facts.(Brode, P.F.III and D.S.Rauch, LANGMUIR, " subtilisin BPN ' " activity on the immobilization substrate ", volume 8,1325-1329 page or leaf (1992)).In fact, when the surface concn of enzyme changes, had been found that the linear relation of surface concn and speed for not dissolving substrate.(Rubingh, D.N. and M.D.Bauer. " catalytic hydrolysis of the proteolytic enzyme on the protein soln interface " polymer solution: mixed and interface (, POLYMER SOLUTIONS, BLENDSAND INTERFACES), I.Noda and D.N.Rubingh, Elsevier writes the 464th page (1992)).Unexpectedly, when attempting that this principle is used to study the varient proteolytic enzyme that obtains better scourability, we can not find to adsorb more enzyme and obtain preferable performance.In fact, we are surprised to find the fact in contrast: the substrate hydrolysis that the absorption of the decline of enzyme-to-substrate causes increasing (that is, scourability) preferably.
Although do not wish to be bound by any theory, we believe, when with varient mutually relatively the time, the performance of improvement is the result of the following fact, promptly adsorbs the also not too closely combination of less enzyme, thereby the surface of not dissolving protein substrate is easier moves desiring to remove.Under comparable enzyme solution concentration, the locomotivity of increase is enough to surpass any advantage by provide the higher concentration enzyme to give to the surface.
The sudden change that the present invention describes is used for the absorption of the dirt of change (promptly reducing) enzyme and surface bonding.In hot enzyme, some amino acid forms outer shroud on the enzyme molecule.In order to discuss, these rings can be described as first, second, third, fourth and the zone, five rings.Specifically, site 66-73 forms the first ring zone; Site 103-115 forms the second ring zone; Site 134-141 forms the 3rd ring zone; Site 162-171 forms the zone, Fourth Ring; Site 191-195 forms the zone, five rings; Form the 6th ring zone (the site numbering is similar to the aminoacid sequence of the hot enzyme of wild-type subtilisin (SEQ ID NO:1)) with site 204-224.
We believe that these ring zones play an important role in the absorption of the peptide of enzyme molecule and surface bonding, concrete sudden change has a significant effect to absorption in one or more rings zone.Although do not wish to be bound by any theory, we believe that at least two reasons these ring zones are important to the absorption of hot enzyme molecule.At first, containing the regional amino acid of ring can contact with any surface that molecule exposes nearly.Secondly, the ring of hot enzyme molecule zone and avtive spot near and combine capsule and make them in the absorption of the catalysis generation of the substrate (peptide/protein dirt) of enzyme and surface bonding, work.
Term used herein " varient " is meant and contains the enzyme that is different from the wild-type amino acid sequence.
Term used herein " hot enzyme dna suddenlys change " refers to the dna sequence dna of the hot enzyme variant body of coding.
Term used herein " the hot enzyme of wild-type " refers to the enzyme of being represented by SEQ ID NO:1.The aminoacid sequence of this hot enzyme is at Meloun, B., and Baudys, M, Kostka, V., Hausdorf, G, Frommel, C., and Hohne, W.E., FEBA LETT. further describes in volume 183, the 195-200 pages or leaves (classifying reference as).
Term used herein " hot enzyme wild-type amino acid sequence " comprises SEQ ID NO:1 and removes site 66,67,68,69,70,72,73,103,104,105,106,107,108,109,110,111,112,113,114,115,134,135,136,137,138,139,140,141,162,163,164,165,166,167,168,169,170,171,191,192,193,194,195,204,205,206,207,208,209,210,211,212,213,214,215,216,217,218,219,220,221,222, outside 223 or 224 to the SEQ ID NO:1 of amino acid sequence modifications.
Term used herein " more hydrophilic amino acid " refers to any other amino acid that has bigger hydrophilicity value with reference to the hydrophilicity value in the following table than target amino acid.Following hydrophilicity value table (table 1) with the descending order of the hydrophilicity value that increases list amino acid (referring to Hopp, T.P., and Woods.K.R., " judge the proteantigen determinant ", institute of NAS periodical, volume 78 by aminoacid sequence, the 3824-3828 page or leaf, 1981, classify reference as).
Table 1 amino acid hydrophilicity value Trp-3.4 Phe-2.5 Tyr-2.3Leu, Ile-1.8 Val-1.5 Met-1.3 Cys-1.0Ala, His-0.5 Thr-0.4Pro, Gly-0.0Gln, Asn 0.2 Ser 0.3Arg +, Lys +, Glu -, Asp -3.0
Table l has also illustrated and has had electric charge (this feature is based on the pH of about 8-9).The amino acid of positive charge is Arg and Lys, and negative charge amino acid is Glu and Asp, and remaining amino acid is neutral.In a preferred embodiment of the invention, substituted amino acid is neutral or negative charge, more preferably negative charge (being Glu or Asp).
Thereby, for example explanation " with equate more hydrophilic neutrality or have the Gln of the aminoacid replacement of negative charge " refer to Gln with Asn (it equates with the wetting ability of Gln) or Ser, Glu or Asp (they are more hydrophilic than Gln) replacement.They each all be neutral or have negative charge, compares with Gln, and they have bigger hydrophilicity value.Equally, illustrate that " with more hydrophilic neutrality or have the Pro of the aminoacid replacement of negative charge " refers to the Pro that replaces with Gln, Asn, Ser, Glu or Asp.
In one embodiment of the invention, hot enzyme variant body has the modified amino acid sequence of hot enzyme wild-type amino acid sequence, and wherein the wild-type amino acid sequence contains the substituting group on one or more sites in regional one or more of the first ring zone, the second ring zone, the 3rd ring zone, zone, Fourth Ring, zone, five rings or the 6th ring; Thereby hot enzyme variant body is compared with the hot enzyme of wild-type, has the hydrolytic action of the adsorption and the increase of reduction to not dissolving substrate.
In a preferred embodiment of the invention, one or more sites substituted amino acid in one or more rings zone, reference table 1, be neutral or negative charge, comparing with the amino acid of target site in the wild-type aminoacid sequence, is equal or more hydrophilic, preferably more hydrophilic.A. the replacement in the first ring zone
When replacement occurs in the first ring zone, replace and to occur on site 66,67,68,69,70,72 or 73 one or more.
When replacement occurred in site 66, substituted amino acid was Asn, Asp, Glu or Ser.
When replacement occurred in site 67, substituted amino acid was Asn, Asp, Glu or Ser.
When replacement occurred in site 68, substituted amino acid was Asn, Asp, Gln, Glu, Pro or Ser.
When replacement occurred in site 69, substituted amino acid was Asp, Gln, Glu or Ser.
When replacement occurred in site 70, substituted amino acid was Asn, Asp, Gln, Glu, Pro or Ser.
When replacement occurred in site 72, substituted amino acid was Asn, Asp, Gln, Glu, Pro or Ser.
When replacement occurred in site 73, substituted amino acid was Asn, Asp, Gln, Glu, Gly, Pro or Ser.B. the replacement in the second ring zone
When replacement occurs in the second ring zone, replace and to occur on site 103,104,105,106,107,108,109,110,111,112,113,114 or 115 one or more.
When replacement occurred in site 103, substituted amino acid was Ala, Asn, Asp, Cys, Gln, Glu, Gly, His, Met, Pro, Ser or Thr.
When replacement occurred in site 104, substituted amino acid was Ala, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Met, Pro, Ser, Thr or Val.
When replacement occurred in site 105, substituted amino acid was Glu.
When replacement occurred in site 106, substituted amino acid was Asp, Gln, Glu or Ser.
When replacement occurred in site 107, substituted amino acid was Asp or Glu.
When replacement occurred in site 108, substituted oxy acid was Asn, Asp, Gln, Glu, Pro or Ser.
When replacement occurred in site 109, substituted amino acid was Asp or Glu.
When replacement occurred in site 110, substituted amino acid was Asn, Asp, Gln, Glu, Pro or Ser.
When replacement occurred in site 111, substituted amino acid was Asn, Asp, Gln, Glu, Gly, Pro or Ser.
When replacement occurred in site 112, substituted amino acid was Ala, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Met, Phe, Pro, Ser, Thr, Tyr or Val.
When replacement occurred in site 113, substituted amino acid was Asn, Asp, Gln, Glu, Gly, Pro or Ser.
When replacement occurred in site 114, substituted amino acid was Asn, Asp, Gln, Glu, Gly, His, Pro, Ser or Thr.
When replacement occurred in site 115, substituted amino acid was Ala, Asn, Asp, Cys, Gln, Glu, Gly, His, Met, Pro, Ser or Thr.C. the replacement in the 3rd ring zone
When replacement occurs in the 3rd ring zone, replace to take place on site 134,135,136,137,138,139,140 or 141 one or more.Wherein
When replacement occurred in site 134, substituted amino acid was Ala, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Met, Pro, Ser, Thr or Val.
When replacement occurred in site 135, substituted amino acid was Asn, Asp, Gln, Glu, Pro or Ser.
When replacement occurred in site 136, substituted amino acid was Asn, Asp, Gln, Glu, Pro or Ser.
When replacement occurred in site 137, substituted amino acid was Asn, Asp, Gln, Glu, Gly, Pro or Ser.
When replacement occurred in site 138, substituted amino acid was Ala, Asn, Asp, Cys, Gln, Glu, Gly, His, Met, Pro, Ser or Thr.
When replacement occurred in site 139, substituted amino acid was Asn, Asp, Gln, Glu, Pro or Ser.
When replacement occurred in site 140, substituted amino acid was Asp, Gln, Glu or Ser.With
When replacement occurred in site 141, substituted amino acid was Asp or Glu.D. the replacement in the zone, Fourth Ring
When replacement occurs in the zone, Fourth Ring, replace and to occur on site 162,163,164,165,166,167,168,169,170 or 171 one or more.
When replacement occurred in site 162, substituted amino acid was Asn, Asp, Gln, Glu, Pro or Ser.
When replacement occurred in site 163, substituted amino acid was Asp, Gln, Glu or Ser.
When replacement occurred in site 164, substituted amino acid was Asn, Asp, Gln, Glu, Gly, His, Pro, Ser or Thr.
When replacement occurred in site 165, substituted amino acid was Asn, Asp, Gln, Glu, Pro or Ser.
When replacement occurred in site 166, substituted amino acid was Asp, Gln, Glu or Ser.
When replacement occurred in site 167, substituted amino acid was Asn, Asp, Gln, Glu, Gly, Pro or Ser.
When replacement occurred in site 168, substituted amino acid was Asn, Asp, Gln, Glu, Gly, His, Pro, Ser or Thr.
When replacement occurred in site 169, substituted amino acid was Asn, Asp, Gln, Glu, Gly or Ser.
When replacement occurred in site 170, substituted amino acid was Asp, Gln, Glu or Ser; With
When replacement occurred in site 171, substituted amino acid was Ala, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Met, Pro, Ser, Thr or Val.E. the replacement in the zone, five rings
When replacement occurs in the zone, five rings, replace occur in site 191,192,193,194 or 195 one or more on.
When replacement occurred in site 191, substituted amino acid was Asp or Glu.
When replacement occurred in site 192, substituted amino acid was Asp or Glu.
When replacement occurred in site 193, substituted amino acid was Ala, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Met, Pro, Ser, Thr, Tyr or Val.
When replacement occurred in site 194, substituted amino acid was Asp or Glu.
When replacement occurred in site 195, substituted amino acid was Asn, Asp, Gln, Glu, Gly, Pro or Ser.Replacement in F the 6th ring zone
When replacement occurs in the 6th ring zone, replace and to occur on site 204,205,206,207,208,209,210,211,212,213,214,215,216,217,218,219,220,221,222,223 or 224 one or more.
When replacement occurred in site 204, substituted amino acid was Asn, Asp, Gln, Glu, Gly, His, Pro, Ser or Thr.
When replacement occurred in site 205, substituted amino acid was Asn, Asp, Gln, Glu, Gly or Ser.
When replacement occurred in site 206, substituted amino acid was Asn, Asp, Gln, Glu, Pro or Ser.
When replacement occurred in site 207, substituted amino acid was Asp or Glu.
When replacement occurred in site 208, substituted amino acid was Ala, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Met, Phe, Pro, Ser, Thr, Tyr or Val.
When replacement occurred in site 209, substituted amino acid was Ala, Asn, Asp, Cys, Gln, Glu, Gly, His, Leu, Met, Pro, Ser, Thr or Val.
When replacement occurred in site 210, substituted amino acid was Ala, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Met, Pro, Ser, Thr or Val.
When replacement occurred in site 211, substituted amino acid was Asp or Glu.
When replacement occurred in site 212, substituted amino acid was Asn, Asp, Gln, Glu, Gly, Pro or Ser.
When replacement occurred in site 213, substituted amino acid was Ala, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Met, Phe, Pro, Ser, Thr or Val.
When replacement occurred in site 214, substituted amino acid was Asn, Asp, Gln, Glu, Gly or Ser.
When replacement occurred in site 215, substituted amino acid was Asn, Asp, Gln, Glu, Gly, Pro or Ser.
When replacement occurred in site 216, substituted amino acid was Asp or Glu.
When replacement occurred in site 217, substituted amino acid was Asn, Asp, Gln, Glu, Gly, Pro or Ser.
When replacement occurred in site 218, substituted amino acid was Ala, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Met, Pro, Ser, Thr or Val.
When replacement occurred in site 219, substituted amino acid was Asn, Asp, Gln, Glu, Gly, His, Pro, Ser or Thr.
When replacement occurred in site 220, substituted amino acid was Asp or Glu.
When replacement occurred in site 221, substituted amino acid was Ala, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Met, Pro, Ser, Thr or Val.
When replacement occurred in site 222, substituted amino acid was Asp or Glu.
When replacement occurred in site 223, substituted amino acid was Asn, Asp, Gln, Glu, Pro or Ser.
When replacement occurred in site 224, substituted amino acid was Asn, Asp, Gln, Glu, Gly, Pro or Ser.G. the preparation of enzyme variant body
Embodiment 1
Sudden change body heat enzyme dna
Made up the phagemid (" TP ") that contains the hot enzyme gene of wild-type.2.8Kbp Pvu II restriction enzyme fragment (Vieira with plasmid pUC119, J. and Messing, J, " preparation of the plasmid DNA of strand ", 153 Enzymology method 3-11 (1989)) be cloned into plasmid pUB110 (Bacillus GeneticStock Center, Columbus, PvuII site OH1E9).PUC 119-pUB110 hybrid plasmid is called as pJMA601.Be cloned into the hot enzyme gene of PCR amplification with TP at the Bam of pJMA601 H1 restriction site.Phagemid TP is transformed into intestinal bacteria Ung-bacterial strain CJ236, with VCSM13 helper phage (Kunkel, T.A, J.D.Roberts and R.A.Zakour, " need not the quick and effective rite-directed mutagenesis of Phenotypic Selection ", Enzymology method, volume 154,367-382 page or leaf (1987); By Yuckenberg, P.D., F.Witney, J.Geisselsoder and J.McClary improve, and " use contains the DNA of uridylic and the external rite-directed mutagenesis of phagemid carrier ", rite-directed mutagenesis operational guidance M.J.McPherson compiles, 27-48 page or leaf (1991); All classify this paper reference as) the preparation strand contain the ura DNA template.Use single primer site-directed mutagenesis modifying method (Zoller of Zoller and Smith method, M.J. with M Smith, " the oligonucleotide directed mutagenesis of use M13 deutero-carrier: a kind of effective and common method of preparation point mutation in any fragment of DNA ", the research of nuclear ester, volume 10,6487-6500 page or leaf (1982) is classified this paper reference as) prepare all mutant (basically as people such as above-mentioned Yuckenberg, 1991 in explanation).Oligonucleotide uses the preparation of Applied Biosystem Inc.380B dna synthesizer.The jump reaction product is transferred among the coli strain MM294 (American type culture collection intestinal bacteria 33625).All mutant are confirmed by dna sequencing, separated DNA is transformed into the (Yang to subtilis expression strain BG2036, M.Y., E.Ferrari and D.J.Henner, (1984), " clone of the neutral protease gene of subtilis and cloned genes are used to produce the external deletion mutantion that obtains ", bacteriology magazine, volume 160, the 15-21 page or leaf).For some mutant, the modification TP that is used in frameshit terminated codon mutation in the respective rings prepares the uridylic template.Oligonucleotide is used for recovering suitable reading frame and is coded in site 66,67,68,69,70,72,73,103,104,105,106,107,108,109,110,111,112,113,114,115,134,135,136,137,138,139,140,141,162,163,164,165,166,167,168,169,170,171,191,192,193,194,195,204,205,206,207,208,209,210,211,212,213,214,215,216,217,218,219,220,221,222,223 or 224 replacement at random (in these codons for all three kinds of all four kinds of oligonucleotide of base etc. the mole and/or variable mixture).Proofread and correct the ability explanation of the sudden change of frameshit termination and preparation functional enzyme by their casein digestions.Replace at random with dna sequencing and determine.
Embodiment 2
Fermentation
Bacillus subtilis mycetocyte (BG2036) being cultured in 1 liter of LB-glucose broth that to contain interested subtilis mutant contrasts mid-term, at the Biostat ED of 10 liters of cumulative volumes fermentor tank (B.Braun Biotech, Inc., Allentown, Pennsylvania) the middle cultivation.Fermention medium contains yeast extract, starch, defoamer, buffer reagent and trace minerals (referring to fermentation, operational guidance, B.McNeil and L.M.Harvey volume, 1990).In the fermentation test process, meat soup keeps constant pH 7.0.Adding paraxin selects with the microbiotic that carries out the mutagenesis plasmid.Cell is about 60 to A600 37 ℃ of grow overnight, and results.
Embodiment 3
Purify
Fermenting broth is carried out following steps to obtain pure enzyme.By the centrifugal bacillus subtilis mycetocyte of removing in the meat soup, remove thin particle and clarify by block film with 100K.Block on the film concentrating then with 10K, carry out the fluid dialysis, regulate pH to 5.5 with 0.025M MES buffer reagent (2-(N-morpholino) ethyl sulfonic acid) to reduce ionic strength.By enzyme being added cation-exchange chromatography post or affinity adsorption chromatography post, by in the post with sodium-chlor or propylene glycol gradient elution and be further purified (referring to, Scopes, R.K., protein purification theory and practice, Springer-Verlag, NewYork (1984) classifies this paper reference as).
Use pNA test (C.Largman, J.W.Brodrick and M.C.Geokas, the biological chemistry yearbook, volume 99,316-320 page or leaf (1979) is classified this paper reference as for DelMar, E.G.) to be determined at the organized enzyme concentration of the fraction of collecting in the gradient elution process.This experimental measurement is when the synthetic substrate of enzymic hydrolysis dissolved, discharges the speed of p-Nitraniline during succinyl--alanyl-alanyl-prolyl-phenyl alanyl-p-Nitraniline (sAAPF-pNA).Measure hydrolysis reaction with spectrophotometer at 410nm and produce xanchromatic speed, proportional with organized enzyme concentration.In addition, the absorption measurement at 280nm is used for measuring total protein concentration.Organized enzyme/gross protein ratio obtains the purity of enzyme, and is used to identify the fraction as the collection of storage solution.
For avoiding the self-dissolving of enzyme in storage process, in the fraction of the collection that obtains by chromatography column, add the propylene glycol of equal weight.After purification process is finished, SDS-PAGE (sodium dodecyl sulfate-polyacrylamide gel electrophoresis) verification of storage enzyme solution, with trypsin inhibitor type II-T: (St.Louis, Missouri) the turkey white of an egg of Gou Maiing is through the absolute enzyme concn of active sites titration measuring by Sigma Chemical Company.The transformation ratio of measuring will illustrate that the change of different loci generation in the enzyme molecule makes the enzyme variant body compare with wild-type dissolving substrate pNA is had the activity of increase.
In the preparation that uses, enzyme storage solution passes through Sephadex-G25 (Pharmacia, Piscataway, New Jersey) size exclusion post to remove propylene glycol and exchange buffering agent.With the MES buffer reagent of the 0.1M Tris buffer reagent that contains 0.01M calcium chloride (three (hydroxymethyl-amino) methane) replacement in enzyme storage solution, regulate pH to 8.6 with hydrochloric acid.Under 25 ℃ of constant temperature, in the Tris buffer reagent, under pH8.6, carry out all tests.H. the characteristic of enzyme variant body
Embodiment 4
The model surface preparation
The hole glass (CPG) of the aminopropyl control of being bought by CPG Inc. (Fairfield, New Jersey) is as covalently bound by Bachem, Inc. (Torence, California) carrier of the sAAPD-pNA substrate of Gou Maiing.Be reflected in the dimethyl sulfoxide (DMSO) and carry out, (EDC) make coupling agent with (1-ethyl-3-[3-(dimethylamino) propyl group] carbodiimide hydrochloride).After reaction is finished, (use the pNA test monitoring), remove excessive solvent, with dimethyl sulfoxide (DMSO) (DMSO) and bi-distilled water rinsing CPG:sAAPF-pNA.Nitrogen purging is dry under about 70 ℃ in baking oven then.The preparation method of reaction scheme and fixed substrate such as Brode, P.F.III, and D.S.Rauch, " subtilisin BPN ': the activity on immobilized substrate ", LANGMUIR describes in the volume 8,1325-1329 page or leaf (1992) (classifying this paper reference as) and carries out.
CPG contains on the surface 62000 ± 7000pNA molecule/μ m 250.0m from the CPG of CPG Inc. report 2The value of/g, surface-area keep not becoming.This explanation is used for not destroying pore structure (mean diameter 486A) in the method for CPG adding sAAPf-pNA.
Embodiment 5
The surface hydrolysis test
Use CPG:sAAPf-pNA, the hydrolysis of the absorption of enzyme variant body and CPG-bonded peptide can be measured in same test.In the flask of the CPG:sAAPF-pNA that contains the Tris buffer reagent and outgased, add a spot of enzyme variant body storage solution.Flask vibrated 90 minutes in the vibrator of piston action, during this period, with different timed interval failure of oscillations devices (for example, in the initial period of adsorption of hydrolyzation effect, for example initial 20 minutes for per 2 minutes-when experiment finishes, be per 10 minutes).CPG:sAAPF-pNA is left standstill, sampling solution.As people such as above-mentioned Brode, adsorb experimentation and calculating described in 1991 with hydrolysis.
Measure the self-dissolving stability of all enzymes, in the time of experiment, should not show tangible self-dissolving loss.Therefore, enzyme absorption can be measured by measuring solution consumption.The amount of the enzyme variant body that initial enzyme variant bulk concentration and the difference between the concentration of each interlude point measurement obtain adsorbing.Measure by the absorption reading of sample when the 410nm by the amount of the pNA of surface hydrolysis.The total amount of the pNA of hydrolysis adds the amount calculating that remains in the flask by the amount of sampling.This value is calibrated by deducting when not having enzyme under pH8.6 by the amount of the pNA of Tris buffer reagent hydrolysis.According to the efficient of enzyme, benchmark hydrolysis scope is the 7-29% of total hydrolysis.
Embodiment 6
The dynamic analysis of solubilized substrate
The hydrolysis rate of solubilized substrate sAAPF-pNA is monitored by measuring as the absorption increment of the function of time under 410nm with the DU-70 spectrophotometer.It is constant that enzyme concn keeps, and be prepared into the scope of 6-10 nmole, and for each kinetic determination, concentration of substrate changes between 90-700 μ MsAAPF-pNA.In 900 seconds time, per second is collected the adsorption number strong point, and data transfer is to LOTUSTM recording paper (Lotus Development Corporation, Cambridge, Massachu setts).Carry out the analysis of kinetic parameter with standard Linewweaver Burk analytical method, wherein in the data fit of test initial (being generally first few minutes) in the linear regression curve to obtain v OThe v that marks and draws in standard mode reciprocal OAnd s OData obtain K MAnd K CatThe example of I. hot enzyme variant body
The hot enzyme variant body of the present invention of the adsorption of the substrate of reduction surface bonding and the hydrolytic action of increase illustrates in as following table 2-36.In the concrete sudden change of describing, at first provide the original amino acid that occurs in the wild-type, secondly be the site numbering, the 3rd is substituted amino acid.
Table 2
Ring 1-single mutation varient
Gln66Asn
Gln66Asp
Gln66Glu
Gln66Ser
Asn67Asp
Asn67Gln
Asn67Glu
Asn67Ser
Gly68Asn
Gly68Asp
Gly68Gln
Gly68Glu
Gly68Pro
Gly68Ser
Asn69Asp
Asn69Gln
Asn69Glu
Asn69Ser
Gly70Asn
Gly70Asp
Gly70Gln
Gly70Glu
Gly70Pro
Gly70Ser
Gly72Asn
Gly72Asp
Gly72Gln
Gly72Glu
Gly72Pro
Gly72Ser
Thr73Asn
Thr73Asp
Thr73Gln
Thr73Glu
Thr73Gly
Thr73Pro
Thr73Ser
Table 3
the two sudden change of ring 1-variant Asn68Asp, +, Gly72ProGly69Asn, +, Thr73ProAsn66Glu, +, Gly69SerAsn66Glu, +, Gly67SerGly69Gln, +, Thr73ProGly67Ser, +, Gly72SerGly67Asp, +, Thr73GlyGly69Pro, +, Ser70AspGly67Pro, +, Gly69ProAsn66Glu, +, Thr73GlyGly69Gln, +, Gly72AspAsn66Gln, +, Thr73GlyAsn68Asp, +, Thr73SerAsn66Gln, +, Gly69AsnGly67Glu, +, Thr73SerGly72Glu, +, Thr73ProAsn66Glu, +, Thr73ProGly72Asp, +, Thr73GlnAsn68Ser, +, Gly69GluGly67Pro, +, Gly69SerGly67Pro, +, Gly72AspGly69Ser, +, Gly72GluSer70Asp, +, Thr73GlnGly67Ser, +, Asn68GluGly69Ser, +, Thr73SerAsn68Asp, +, Gly69SerAsn66Ser, +, Gly72AspGly69Asp, +, Gly72SerAsn68Ser, +, Thr73ProSer70Asp, +, Thr73SerSer70Glu, +, Gly72AsnGly69Asp, +, Thr73ProGly67Glu, +, Thr73GlyGly72Asp, +, Thr73SerSer70Asp, +, Thr73AsnAsn66Ser, +, Gly69GluGly72Ser, +, Thr73GlnSer70Glu, +, Thr73SerAsn66Gln, +, Gly69Ser
Table 4
ring 1-three sudden change variant Ser70Asp, +, Gly72Gln, +, Thr73GlyGly67Ser, +, Asn68Gln, +, Ser70AspAsn66Ser, +, Gly67Asn, +, Thr73GlnAsn66Gln, +, Ser70Asp, +, Gly72AsnSer70Glu, +, Gly72Gln, +, Thr73SerGly67Pro, +, Asn68Glu, +, Thr73SerAsn66Ser, +, Gly69Gln, +, Gly72GlnAsn66Ser, +, Ser70Asp, +, Thr73GlnGly67Gln, +, Gly69Asp, +, Thr73GlnGly69Pro, +, Gly72Glu, +, Thr73SerGly67Gln, +, Gly69Asn, +, Thr73AsnAsn66Ser, +, Gly69Asp, +, Thr73AsnGly69Asp, +, Gly72Ser, +, Thr73SerAsn68Asp, +, Gly72Gln, +, Thr73SerAsn66Gln, +, Asn68Ser, +, Thr73AsnAsn68Ser, +, Gly69Ser, +, Ser70AspAsn68Gln, +, Gly69Ser, +, Thr73GlnGly67Ser, +, Gly69Pro, +, Gly72GluGly67Asn, +, Gly69Ser, +, Thr73AsnGly67Gln, +, Gly72Asn, +, Thr73GlnGly67Pro, +, Asn68Gln, +, Gly69ProGly69Asn, +, Ser70Glu, +, Thr73SerAsn66Ser, +, Ser70Glu, +, Gly72AsnGly69Gln, +, Ser70Asp, +, Gly72AsnGly67Ser, +, Ser70Glu, +, Thr73GlnAsn66Glu, +, Gly67Gln, +, Thr73ProGly67Ser, +, Gly72Glu, +, Thr73SerGly67Pro, +, Gly69Gln, +, Gly72AspAsn66Ser, +, Gly67Glu, +, Thr73ProAsn66Ser, +, Gly67Glu, +, Asn68SerGly67Asn, +, Asn68Glu, +, Gly69AspAsn68Glu, +, Gly69Glu, +, Gly72ProAsn68Glu, +, Gly69Glu, +, Thr73AsnGly67Glu, +, Asn68Asp, +, Gly69GlnGly67Glu, +, Asn68Asp, +, Thr73GlnAsn66Asp, +, Gly67Asp, +, Gly72SerAsn66Glu, +, Gly67Glu, +, Thr73Pro
Table 5
ring 1-four sudden change variant Asn66Gln, +, Gly67Ser, +, Gly69Asp, +, Gly72ProAsn68Ser, +, Ser70Glu, +, Gly72Gln, +, Thr73ProAsn66Gln, +, Gly67Gln, +, Ser70Asp, +, Thr73AsnGly67Ser, +, Gly69Asp, +, Gly72Gln, +, Thr73GlyAsn66Glu, +, Gly67Ser, +, Asn68Ser, +, Thr73AsnGly67Ser, +, Asn68Asp, +, Gly72Asn, +, Thr73GlyAsn66Ser, +, Gly67Glu, +, Gly69Gln, +, Thr73GlyAsn68Glu, +, Gly69Asp, +, Gly72Asn, +, Thr73AsnGly67Glu, +, Asn68Glu, +, Gly72Asn, +, Thr73AsnAsn66Glu, +, Gly67Glu, +, Asn68Gln, +, Gly72ProAsn66Glu, +, Gly67Glu, +, Asn68Ser, +, Gly72AsnAsn66Glu, +, Gly67Glu, +, Gly72Pro, +, Thr73AsnGly67Ser, +, Gly69Asp, +, Ser70Glu, +, Thr73GlnAsn66Ser, +, Gly69Glu, +, Ser70Glu, +, Thr73GlyGly67Pro, +, Asn68Glu, +, Gly69Glu, +, Ser70GluGly67Ser, +, Asn68Glu, +, Gly69Asp, +, Ser70AspGly67Asn, +, Asn68Asp, +, Gly69Asp, +, Ser70GluGly67Asp, +, Asn68Gln, +, Gly69Glu, +, Ser70AspAsn66Gln, +, Gly67Asp, +, Gly69Asp, +, Ser70AspGly67Asp, +, Asn68Asp, +, Ser70Asp, +, Thr73AsnGly67Asp, +, Asn68Asp, +, Gly69Pro, +, Ser70GluGly67Asp, +, Asn68Gln, +, Ser70Glu, +, Gly72ProAsn66Gln, +, Gly67Glu, +, Ser70Asp, +, Gly72GlnGly67Glu, +, Ser70Glu, +, Gly72Gln, +, Thr73SerGly67Asp, +, Asn68Gln, +, Ser70Asp, +, Gly72SerGly67Glu, +, Ser70Asp, +, Gly72Ser, +, Thr73Ser
Table 6
Ring 2-single mutation varient
Val103Ala
Val103Asn
Val103Asp
Vsl103Gln
Val103Gln
Val103Glu
Val103Gly
Val103His
Val103Met
Val103Pro
Val103Ser
Val103Thr
Leu104Ala
Leu104Asn
Leu104Asp
Leu104Cys
Leu104Gln
Leu104Glu
Leu104Gly
Leu104His
Leu104Ile
Leu104Met
Leu104Pro
Leu104Ser
Leu104Thr
Leu104Val
Asp105Glu
Asn106Asp
Asn106Gln
Asn106Glu
Asn106Ser
Ser107Asp
Ser107Glu
Gly108Asn
Gly108Asp
Gly108Gln
Gly108Glu
Gly108Pro
Gly108Ser
Ser109Asp
Ser109Glu
Gly110Asn
Gly110Asp
Gly110Gln
Gly110Glu
Gly110Pro
Gly110Ser
Thr111Asn
Thr111Asp
Thr111Gln
Thr111Glu
Thr111Gly
Thr111Pro
Thr111Ser
Trp112Ala
Trp112Asn
Trp112Asp
Trp112Cys
Trp112Gln
Trp112Glu
Trp112Gly
Trp112His
Trp112Ile
Trp112Leu
Trp112Met
Trp112Phe
Trp112Pro
Trp112Ser
Trp112Thr
Trp112Tyr
Trp112Val
Thr113Asn
Thr113Asp
Thr113Gln
Thr113Glu
Thr113Gly
Thr113Pro
Thr113Ser
Ala114Asn
Ala114Asp
Ala114Gln
Ala114Glu
Ala114Gly
Ala114His
Ala114Pro
Ala114Ser
Ala114Thr
Val115Ala
Val115Asn
Val115Asp
Val115Cys
Val115Gln
Val115Glu
Val115Gly
Val115His
Val115Met
Val115Pro
Val115Ser
Val115Thr
Table 7
the two sudden change of ring 2-variant Val103Gln, +, Ser109GluAsp105Glu, +, Gly108GlnAsp105Glu, +, Gly110AsnAsp105Glu, +, Gly110ProVal103Asp, +, Thr111GlnLeu104Gln, +, Gly108AspLeu104Gly, +, Ser107GluThr111Pro, +, Ala114SerAsn106Gln, +, Ser109AspAsp105Glu, +, Gly108ProThr113Asp, +, Val115GlyVal103Met, +, Leu104GlnGly108Gln, +, Thr113AsnGly110Glu, +, Ala114GlyThr111Gln, +, Val115GlnGly110Glu, +, Thr111GlnGly108Pro, +, Ala114GluGly108Ser, +, Val115GlyAsp105Glu, +, Thr113GlnLeu104His, +, Ser107AspAsp105Glu, +, Ala114GlnGly110Gln, +, Thr113SerVal103His, +, Ala114GlnAsp105Glu, +, Trp112IleThr111Ser, +, Thr113AspLeu104His, +, Thr111GluAsn106Gln, +, Trp112TyrLeu104Gly, +, Thr113GlnVal103Thr, +, Val115AsnVal103Thr, +, Asn106SerVal103Pro, +, Thr111ProSer109Glu, +, Val115MetVal103Ala, +, Asn106GlnVal103Cys, +, Thr111GlnTrp112Gly, +, Thr113GlyVal103Gly, +, Asp105GluGly110Asn, +, Thr113GlyThr111Asn, +, Thr113GluVal103Glu, +, Trp112MetLeu104Pro, +, Ser109AspGly108Gln, +, Ala114GlyLeu104Met, +, Val115GluLeu104Gly, +, Ala114SerThr113Ser, +, Val115AlaAsp105Glu, +, Asn106GlnVal103Thr, +, Asp105GluGly110Glu, +, Val115MetVal103Gly, +, Gly110GluSer109Asp, +, Gly110GlnThr111Asp, +, Ala114SerAsn106Glu, +, Ala114ProSer109Glu, +, Thr113GlyGly108Asn, +, Trp112GluVal103Pro, +, Asn106GluAsp105Glu, +, Trp112LeuLeu104Cys, +, Asp105GluLeu104Cys, +, Thr111SerLeu104Thr, +, Ser109AspVal103Asn, +, Val115GluVal103Ser, +, Gly108Glu
Table 8
ring 2-three sudden change variant Val103Gln, +, Leu104Thr, +, Ser109GluLeu104Ser, +, Asp105Glu, +, Trp112PheAsn106Gln, +, Gly108Ser, +, Gly110GlnSer109Asp, +, Thr111Asn, +, Trp112ThrAsn106Ser, +, Gly108Gln, +, Ser109AspAsp105Glu, +, Gly108Pro, +, Val115GlyAsn106Ser, +, Ser107Asp, +, Val115GlyAsn106Ser, +, Trp112Gln, +, Val115GluLeu104Pro, +, Ser109Asp, +, Thr113GlyLeu104Asp, +, Gly110Gln, +, Val115ProGly108Asn, +, Thr111Ser, +, Ala114ProLeu104Ser, +, Asn106Ser, +, Thr111GluVal103His, +, Leu104Gln, +, Asn106AspAsn106Gln, +, Trp112Asn, +, Ala114AspVal103Met, +, Gly110Pro, +, Thr111ProLeu104Thr, +, Gly108Glu, +, Gly110AsnLeu104Ala, +, Ser109Asp, +, Trp112CysGly108Glu, +, Gly110Pro, +, Val115GlyLeu104Pro, +, Thr113Asn, +, Ala114AspVal103Asn, +, Leu104Met, +, Asn106GluVal103Cys, +, Ser109Glu, +, Val115CysVal103Gly, +, Leu104Val, +, Ser107AspGly108Pro, +, Ser109Glu, +, Trp112GlnLeu104Met, +, Trp112Cys, +, Thr113AsnAsn106Asp, +, Trp112Ile, +, Ala114SerVal103Gly, +, Ser109Glu, +, Ala114ProLeu104Ile, +, Trp112Leu, +, Thr113GlyAsn106Gln, +, Gly108Asn, +, Ser109GluVal103Asn, +, Trp112Pro, +, Ala114AspGly108Asn, +, Gly110Ser, +, Trp112GlyGly110Asp, +, Trp112Leu, +, Val115HisVal103Gly, +, Leu104Gly, +, Gly108AspLeu104Ala, +, Thr111Ser, +, Val115AlaThr111Ser, +, Thr113Asn, +, Val115HisAsp105Glu, +, Gly108Gln, +, Val115GlyLeu104Gly, +, Ala114Ser, +, Val115AlaVal103His, +, Leu104Gly, +, Asn106GluVal103Ser, +, Gly110Glu, +, Thr113ProVal103Pro, +, Gly110Asn, +, Ala114GluLeu104Met, +, Gly110Asp, +, Val115ProLeu104Asp, +, Thr111Gln, +, Trp112AlaSer109Asp, +, Gly110Pro, +, Trp112AsnLeu104Asp, +, Asp105Glu, +, Trp112CysGly108Glu, +, Ser109Glu, +, Ala114ThrGly108Asp, +, Ser109Asp, +, Thr111ProGly108Glu, +, Ser109Glu, +, Ala114AsnAsn106Ser, +, Ser109Glu, +, Gly110AspAsn106Gln, +, Ser109Asp, +, Gly110AspVal103Asp, +, Leu104Asp, +, Gly108ProLeu104Thr, +, Asp105Glu, +, Asn106GluAsp105Glu, +, Asn106Asp, +, Thr113AsnGly108Gln, +, Thr113Glu, +, Ala114GluLeu104Ser, +, Thr111Glu, +, Trp112GluAsn106Asp, +, Ser107Asp, +, Gly108AspAsp105Glu, +, Ser109Asp, +, Gly110GluTrp112Ala, +, Thr113Asp, +, Val115AspVal103Gln, +, Asp105Glu, +, Gly108AspLeu104Gln, +, Asp105Glu, +, Ser107GluSer107Asp, +, Ser109Asp, +, Thr111GlyVal103Cys, +, Ser107Asp, +, Ser109Glu
Table 9
ring 2-four sudden change variant Asp105Glu, +, Gly110Ser, +, Trp112Phe, +, Thr113SerVal103Ala, +, Ser107Asp, +, Gly110Pro, +, Ala114AsnVal103Gln, +, Gly108Pro, +, Thr111Ser, +, Ala114GluVal103Thr, +, Ser107Asp, +, Thr113Gln, +, Val115CysLeu104Asn, +, Gly110Ser, +, Thr113Glu, +, Val115GlnVal103Pro, +, Gly108Glu, +, Trp112His, +, Val115MetVal103Ala, +, Asn106Ser, +, Gly108Asp, +, Thr111AsnVal103Ala, +, Leu104Asp, +, Gly110Ser, +, Val115AlaSer109Glu, +, Trp112Pro, +, Ala114Asn, +, Val115MetVal103Thr, +, Asn106Asp, +, Gly108Ser, +, Gly110GlnVal103Pro, +, Leu104Pro, +, Asn106Ser, +, Gly110AsnSer109Glu, +, Gly110Pro, +, Thr111Ser, +, Thr113SerAsn106Gln, +, Gly108Ser, +, Trp112Tyr, +, Ala114ThrLeu104Cys, +, Gly110Gln, +, Thr111Asp, +, Thr113GlyLeu104Ser, +, Asp105Glu, +, Gly108Gln, +, Val115AsnVal103Asp, +, Gly108Asn, +, Thr113Pro, +, Ala114ProVal103Asp, +, Leu104Asn, +, Thr113Asn, +, Val115AlaVal103Asn, +, Gly110Asp, +, Thr111Asn, +, Val115CysVal103Ser, +, Asn106Glu, +, Gly110Gln, +, Val115MetLeu104Val, +, Thr111Gln, +, Trp112His, +, Ala114SerLeu104Ser, +, Asp105Glu, +, Gly110Gln, +, Thr111AsnVal103Ala, +, Asp105Glu, +, Asn106Ser, +, Gly110AsnVal103Glu, +, Gly110Ser, +, Trp112Phe, +, Val115GlyAsn106Glu, +, Thr113Asn, +, Ala114Pro, +, Val115AsnLeu104Glu, +, Asp105Glu, +, Gly108Ser, +, Gly110AsnGly108Glu, +, Ser109Glu, +, Thr111Asn, +, Ala114ProGly108Glu, +, Ser109Glu, +, Thr111Gln, +, Ala114ThrLeu104Ile, +, Gly108Pro, +, Ser109Glu, +, Gly110AspVal103Glu, +, Leu104Asp, +, Trp112Cys, +, Thr113SerAsp105Glu, +, Asn106Glu, +, Gly110Pro, +, Thr113GlyGly110Gln, +, Thr111Glu, +, Trp112Glu, +, Thr113GlySer107Asp, +, Gly108Asp, +, Ser109Asp, +, Trp112ValAsn106Asp, +, Ser107Asp, +, Gly108Glu, +, Val115ProAsp105Glu, +, Ser107Glu, +, Gly108Asp, +, Gly110SerAsp105Glu, +, Gly108Asp, +, Ser109Glu, +, Thr111GlnAsp105Glu, +, Gly108Glu, +, Ser109Glu, +, Thr111ProLeu104Asp, +, Ser109Glu, +, Trp112Asn, +, Ala114GlyVal103Ser, +, Leu104Glu, +, Gly108Asn, +, Ser109GluAsp105Glu, +, Ser109Glu, +, Gly110Glu, +, Trp112GlnVal103Ser, +, Asp105Glu, +, Gly108Glu, +, Val115ProAsp105Glu, +, Ser107Asp, +, Trp112Leu, +, Thr113GlyLeu104His, +, Asp105Glu, +, Asn106Ser, +, Ser107AspAsp105Glu, +, Ser107Glu, +, Ser109Asp, +, Val115GlnAsp105Glu, +, Ser107Glu, +, Ser109Glu, +, Thr113GlySer107Glu, +, Ser109Glu, +, Thr111Gln, +, Thr113GlnSer107Glu, +, Ser109Glu, +, Trp112Val, +, Val115ProSer107Glu, +, Ser109Glu, +, Trp112Ile, +, Val115GlnAsp105Glu, +, Ser109Glu, +, Gly110Gln, +, Val115ProLeu104Glu, +, Asp105Glu, +, Ser107Glu, +, Ala114GlyAsp105Glu, +, Asn106Glu, +, Gly108Pro, +, Ser109AspLeu104Asn, +, Asp105Glu, +, Gly110Asp, +, Ala114GlySer107Glu, +, Gly108Gln, +, Ser109Asp, +, Gly110AspGly108Gln, +, Gly110Glu, +, Trp112Asp, +, Val115GluVal103Asp, +, Leu104Ser, +, Asp105Glu, +, Val115GlnLeu104Glu, +, Asn106Glu, +, Gly110Glu, +, Val115AsnLeu104Asp, +, Gly110Glu, +, Thr111Ser, +, Trp112AspSer109Asp, +, Gly110Glu, +, Thr113Asn, +, Val115GluVal103Ser, +, Gly108Asp, +, Gly110Glu, +, Thr111GluLeu104Gly, +, Asn106Glu, +, Gly108Asn, +, Ser109GluVal103Asp, +, Leu104Gly, +, Thr111Glu, +, Val115Met
Table 10
Ring 3-single mutation varient
Leu134Ala
Leu134Asn
Leu134Asp
Leu134Cys
Leu134Gln
Leu134Glu
Leu134Gly
Leu134His
Leu134Ile
Leu134Met
Leu134Pro
Leu134Ser
Leu134Thr
Leu134Val
Gly135Asn
Gly135Asp
Gly135Gln
Gly135Glu
Gly135Pro
Gly135Ser
Gly136Asn
Gly136Asp
Gly136Gln
Gly136Glu
Gly136Pro
Gly136Ser
Thr137Asn
Thr137Asp
Thr137Gln
Thr137Glu
Thr137Gly
Thr137Pro
Thr137Ser
Val138Ala
Val138Asn
Val138Asp
Val138Cys
Val138Gln
Val138Glu
Val138Gly
Val138His
Val138Met
Val138Pro
Val138Ser
Val138Thr
Gly139Asn
Gly139Asp
Gly139Gln
Gly139Glu
Gly139Pro
Gly139Ser
Asn140Asp
Asn140Gln
Asn140Glu
Asn140Ser
Ser141Asp
Ser141Glu
Table 11
the two sudden change of ring 3-variant Leu134Val, +, Ser141AspLeu134Val, +, Thr137GluGly135Asn, +, Ser141AspGly135Ser, +, Thr137SerLeu134Met, +, Gly139AspLeu134Thr, +, Gly139GlnGly139Gln, +, Asn140GluGly139Pro, +, Ser141AspLeu134Glu, +, Val138AsnLeu134Asn, +, Val138AlaLeu134Ser, +, Asn140GluVal138Asn, +, Ser141AspGly135Glu, +, Val138SerLeu134Ile, +, Gly139GluLeu134Ile, +, Gly135AsnLeu134Met, +, Asn140AspGly136Ser, +, Gly139AspGly136Pro, +, Val138AsnLeu134Gly, +, Gly135ProLeu134Gly, +, Ser141GluGly135Pro, +, Gly139ProLeu134Thr, +, Gly139ProGly135Glu, +, Asn140SerThr137Gln, +, Gly139AspGly135Asp, +, Asn140SerLeu134Ser, +, Asn140AspGly136Gln, +, Gly139AspLeu134Pro, +, Ser141GluLeu134His, +, Asn140GlnLeu134Pro, +, Gly135GluGly135Pro, +, Gly136AspVal138Thr, +, Ser141AspVal138Pro, +, Ser141AspLeu134Gln, +, Thr137GluVal138Ser, +, Ser141AspVal138Thr, +, Asn140GlnLeu134Glu, +, Val138GlnGly139Asn, +, Ser141GluGly139Pro, +, Ser141GluGly135Gln, +, Gly139GluThr137Pro, +, Val138GlyGly135Asp, +, Gly136GlnGly135Asn, +, Val138ThrThr137Asn, +, Ser141GluGly135Pro, +, Val138GluGly135Glu, +, Thr137SerGly135Asp, +, Gly139ProLeu134Ala, +, Gly135GlnVal138Gln, +, Ser141AspGly135Ser, +, Gly139AspThr137Ser, +, Val138MetLeu134Ala, +, Gly136GlnLeu134Glu, +, Asn140GlnGly136Asn, +, Asn140GlnGly136Gln, +, Ser141AspVal138Ser, +, Ser141GluLeu134Thr, +, Thr137GluGly135Ser, +, Gly139ProVal138Cys, +, Gly139AspThr137Gly, +, Gly139Asp
Table 12
ring 3-three sudden change variant Gly135Ser, +, Val138Cys, +, Ser141AspGly135Gln, +, Thr137Glu, +, Val138CysLeu134Ser, +, Gly135Pro, +, Gly136GluLeu134Pro, +, Val138Cys, +, Asn140SerLeu134Val, +, Gly135Asp, +, Val138MetLeu134Pro, +, Gly135Pro, +, Gly139GluGly135Gln, +, Val138Asp, +, Gly139SerGly136Pro, +, Val138His, +, Ser141AspLeu134Val, +, Gly136Ser, +, Asn140AspThr137Asp, +, Val138Met, +, Gly139GlnLeu134Val, +, Gly136Pro, +, Thr137GlyGly135Gln, +, Val138Gln, +, Asn140AspLeu134His, +, Gly136Glu, +, Asn140GlnGly135Pro, +, Gly139Gln, +, Ser141AspGly136Asn, +, Val138Asn, +, Ser141AspGly135Asp, +, Val138Thr, +, Gly139GlnGly136Pro, +, Thr137Asp, +, Gly139SerLeu134Gly, +, Gly136Gln, +, Gly139SerLeu134Val, +, Gly135Glu, +, Thr137GlyLeu134Thr, +, Val138Gln, +, Gly139SerGly136Asp, +, Thr137Asn, +, Val138GlyGly135Asp, +, Val138Ser, +, Asn140GlnGly136Asn, +, Val138Glu, +, Asn140GlnLeu134Cys, +, Thr137Glu, +, Val138GlyLeu134Asn, +, Gly135Glu, +, Gly139SerGly135Ser, +, Val138His, +, Asn140GluLeu134Ala, +, Gly139Ser, +, Asn140GlnGly135Asp, +, Thr137Pro, +, Val138CysLeu134Cys, +, Val138Gly, +, Asn140AspLeu134Thr, +, Val138Ser, +, Gly139AspLeu134Cys, +, Thr137Gln, +, Ser141GluLeu134Val, +, Gly136Pro, +, Gly139GluLeu134Ala, +, Gly135Asn, +, Ser141GluGly136Gln, +, Thr137Gln, +, Val138ProLeu134Asp, +, Gly135Pro, +, Gly139SerGly135Ser, +, Val138Gly, +, Ser141AspLeu134Val, +, Thr137Asp, +, Gly139GlnLeu134His, +, Gly135Pro, +, Gly139GlnThr137Pro, +, Val138Gln, +, Asn140AspThr137Gln, +, Val138Cys, +, Gly139GluThr137Ser, +, Gly139Glu, +, Asn140GlnGly135Gln, +, Thr137Gln, +, Asn140AspGly135Gln, +, Thr137Gln, +, Val138AspLeu134His, +, Gly139Gln, +, Asn140AspLeu134Ala, +, Thr137Asn, +, Gly139GluVal138Pro, +, Gly139Pro, +, Asn140GlnGly135Asn, +, Asn140Ser, +, Ser141GluLeu134Ile, +, Gly135Asp, +, Val138CysThr137Gln, +, Gly139Ser, +, Asn140SerLeu134Ala, +, Gly136Pro, +, Asn140AspGly135Ser, +, Gly139Asp, +, Asn140SerLeu134Thr, +, Gly135Asn, +, Ser141GluLeu134Gly, +, Thr137Ser, +, Val138AlaLeu134Thr, +, Gly135Gln, +, Val138ProGly135Gln, +, Gly136Asp, +, Thr137SerGly135Ser, +, Val138Thr, +, Asn140AspLeu134Cys, +, Thr137Ser, +, Val138GluGly136Ser, +, Thr137Asn, +, Ser141AspLeu134Thr, +, Gly135Glu, +, Gly139GlnLeu134Thr, +, Gly135Asp, +, Thr137Ser
Table 13
ring 3-four sudden change variant Leu134Met, +, Thr137Pro, +, Asn140Ser, +, Ser141GluLeu134Asn, +, Gly136Pro, +, Thr137Ser, +, Val138GlnLeu134Gln, +, Gly136Gln, +, Val138Ser, +, Gly139SerGly135Glu, +, Gly136Asn, +, Thr137Pro, +, Asn140GlnLeu134Ser, +, Gly136Asn, +, Gly139Gln, +, Ser141GluLeu134Gln, +, Val138Pro, +, Gly139Ser, +, Ser141AspLeu134Pro, +, Gly135Asn, +, Thr137Glu, +, Asn140GlnGly135Asp, +, Thr137Gly, +, Val138Gln, +, Gly139SerLeu134Val, +, Gly135Asp, +, Thr137Asn, +, Asn140SerLeu134Thr, +, Gly135Glu, +, Gly136Ser, +, Thr137SerGly136Pro, +, Thr137Gln, +, Gly139Gln, +, Asn140GluLeu134His, +, Gly135Glu, +, Val138Asn, +, Asn140GlnLeu134Gln, +, Gly135Ser, +, Thr137Asn, +, Ser141GluGly135Gln, +, Gly139Asn, +, Asn140Gln, +, Ser141AspThr137Gln, +, Val138His, +, Gly139Asn, +, Ser141GluLeu134Thr, +, Gly135Gln, +, Val138Thr, +, Asn140AspLeu134Met, +, Gly135Glu, +, Thr137Ser, +, Val138SerVal138Thr, +, Gly139Ser, +, Asn140Ser, +, Ser141GluLeu134Met, +, Gly136Pro, +, Val138Cys, +, Gly139ProLeu134His, +, Gly136Pro, +, Thr137Gln, +, Gly139GluGly135Asn, +, Gly136Gln, +, Val138Cys, +, Ser141GluLeu134Asn, +, Thr137Ser, +, Val138Gln, +, Ser141AspGly135Gln, +, Gly136Pro, +, Thr137Asn, +, Asn140SerGly135Asn, +, Gly139Ser, +, Asn140Gln, +, Ser141AspLeu134Met, +, Gly136Pro, +, Val138Met, +, Ser141GluLeu134Cys, +, Thr137Gln, +, Val138Pro, +, Ser141AspGly136Asn, +, Thr137Gln, +, Gly139Asn, +, Asn140SerLeu134Asn, +, Thr137Ser, +, Gly139Ser, +, Asn140AspGly135Asp, +, Gly136Asp, +, Val138Met, +, Asn140SerGly135Glu, +, Gly136Asp, +, Val138His, +, Gly139GlnLeu134Ser, +, Gly136Glu, +, Thr137Glu, +, Val138ThrLeu134Thr, +, Val138Gln, +, Asn140Glu, +, Ser141GluGly135Gln, +, Thr137Asn, +, Asn140Glu, +, Ser141GluGly135Gln, +, Thr137Gly, +, Val138Asp, +, Gly139AspLeu134Thr, +, Gly135Glu, +, Gly136Asp, +, Thr137AspVal138Asn, +, Gly139Asp, +, Asn140Glu, +, Ser141AspLeu134Ile, +, Gly139Glu, +, Asn140Asp, +, Ser141AspGly136Pro, +, Gly139Glu, +, Asn140Glu, +, Ser141AspLeu134Gln, +, Gly139Asp, +, Asn140Asp, +, Ser141GluLeu134Val, +, Gly136Glu, +, Val138Asp, +, Asn140GlnGly136Asp, +, Thr137Gln, +, Val138Asp, +, Gly139AsnGly136Glu, +, Thr137Glu, +, Val138His, +, Gly139AspLeu134His, +, Thr137Gln, +, Val138Glu, +, Asn140GluLeu134Gly, +, Gly135Ser, +, Thr137Glu, +, Gly139GluLeu134Gln, +, Gly135Pro, +, Thr137Asp, +, Gly139AspLeu134His, +, Gly135Asn, +, Thr137Asp, +, Gly139GluLeu134Val, +, Gly135Glu, +, Thr137Asp, +, Gly139GlnGly135Asn, +, Thr137Ser, +, Gly139Asp, +, Ser141AspLeu134Cys, +, Thr137Asn, +, Gly139Glu, +, Ser141AspLeu134Ile, +, Thr137Pro, +, Gly139Asp, +, Ser141AspLeu134Thr, +, Val138Asn, +, Gly139Glu, +, Ser141AspGly135Pro, +, Thr137Gly, +, Gly139Glu, +, Ser141AspGly136Ser, +, Val138Ala, +, Gly139Glu, +, Ser141GluLeu134Thr, +, Gly139Asp, +, Asn140Ser, +, Ser141AspGly135Ser, +, Thr137Gly, +, Gly139Glu, +, Ser141AspLeu134Met, +, Gly135Asn, +, Gly139Asp, +, Ser141GluThr137Pro, +, Val138Gly, +, Gly139Asp, +, Ser141AspGly136Glu, +, Thr137Pro, +, Val138Gln, +, Gly139AspThr137Asn, +, Val138Glu, +, Gly139Asp, +, Ser141AspLeu134Thr, +, Val138Glu, +, Gly139Glu, +, Ser141Glu
Table 14
Ring 4-single mutation varient
Gly162Asn
Gly162Asp
Gly162Gln
Gly162Glu
Gly162Pro
Gly162Ser
Asn163Asp
Asn163Gln
Asn163Glu
Asn163Ser
Ala164Asn
Ala164Asp
Ala164Gln
Ala164Glu
Ala164Gly
Ala164His
Ala164Pro
Ala164Ser
Ala164Thr
Gly165Asn
Gly165Asp
Gly165Gln
Gly165Glu
Gly165Pro
Gly165Ser
Asn166Asp
Asn166Gln
Asn166Glu
Asn166Ser
Thr167Asn
Thr167Asp
Thr167Gln
Thr167Glu
Thr167Gly
Thr167Pro
Thr167Ser
Ala168Asn
Ala168Asp
Ala168Gln
Ala168Glu
Ala168Gly
Ala168His
Ala168Pro
Ala168Ser
Ala168Thr
Pro169Asn
Pro169Asp
Pro169Gln
Pro169Glu
Pro169Gly
Pro169Ser
Asn170Asp
Asn170Gln
Asn170Glu
Asn170Ser
Tyr171Ala
Tyr171Asn
Tyr171Asp
Tyr171Cys
Tyr171Gln
Tyr171Glu
Tyr171Gly
Tyr171His
Tyr171Ile
Tyr171Leu
Tyr171Met
Tyr171Pro
Tyr171Ser
Tyr171Thr
Tyr171Val
Table 15
the two sudden change of ring 4-variant Ala164Gln, +, Pro169GluAsn163Asp, +, Thr167SerAla164Pro, +, Ala168AspAla164Gln, +, Asn166SerGly165Asp, +, Thr167ProAla164Gln, +, Ala168SerGly165Gln, +, Asn166GlnGly162Gln, +, Asn163GluGly165Gln, +, Thr167GluGly165Ser, +, Ala168GlnAla164Gln, +, Ala168GluAla164His, +, Tyr171MetGly165Pro, +, Pro169GlnGly165Gln, +, Ala168ProGly162Pro, +, Ala164GlyThr167Pro, +, Asn170SerAsn163Gln, +, Tyr171HisAsn163Ser, +, Ala164GlnAla164Asp, +, Asn166GlnGly165Asn, +, Tyr171IleAla168Asp, +, Asn170GlnAsn166Asp, +, Ala168GlyAsn163Glu, +, Thr167SerAsn166Glu, +, Ala168SerGly162Gln, +, Ala168GluGly162Asn, +, Asn170SerAsn163Gln, +, Ala168HisThr167Pro, +, Ala168ThrGly162Asn, +, Gly165GluAsn166Glu, +, Tyr171ProAla168Asn, +, Asn170GlnGly162Glu, +, Thr167SerThr167Asp, +, Tyr171ValGly162Asp, +, Ala168HisGly165Ser, +, Ala168GluThr167Asp, +, Tyr171MetAla168Thr, +, Pro169GlyGly165Ser, +, Pro169GluGly162Glu, +, Ala164ThrAla168Ser, +, Tyr171AspAsn163Ser, +, Gly165ProAla168Asn, +, Tyr171SerAla164Gln, +, Gly165GlnThr167Asp, +, Asn170SerGly165Ser, +, Asn170GlnThr167Gly, +, Tyr171GluGly162Asn, +, Tyr171GlnGly165Asn, +, Asn166GluAla168Thr, +, Tyr171GluGly165Ser, +, Asn166GluThr167Gly, +, Ala168ThrAsn166Asp, +, Ala168AsnPro169Glu, +, Tyr171ValGly162Glu, +, Asn170SerGly162Ser, +, Pro169GlyAla164Asn, +, Asn166GluThr167Gly, +, Asn170AspThr167Glu, +, Asn170SerAsn163Asp, +, Ala164GlnGly165Gln, +, Pro169Glu
Table 16
ring 4-three sudden change variant Ala164Gly, +, Gly165Glu, +, Thr167SerGly162Asn, +, Ala164Thr, +, Asn166AspAla164Asn, +, Gly165Asp, +, Pro169GlnGly165Pro, +, Thr167Asn, +, Pro169GluAla168Gly, +, Pro169Gly, +, Asn170AspGly162Asp, +, Gly165Pro, +, Ala168SerGly165Asp, +, Thr167Asn, +, Tyr171GlyThr167Ser, +, Pro169Asn, +, Tyr171ThrAsn166Ser, +, Ala168Gly, +, Tyr171IleGly165Gln, +, Thr167Pro, +, Ala168GluGly162Ser, +, Asn163Asp, +, Gly165GlnGly165Glu, +, Thr167Gly, +, Ala168SerThr167Gly, +, Ala168Asp, +, Tyr171ValAsn163Ser, +, Gly165Gln, +, Ala168AspAsn163Asp, +, Ala164Gly, +, Gly165AsnAla164Gln, +, Pro169Ser, +, Asn170GlnAla164His, +, Thr167Gln, +, Pro169GlyThr167Ser, +, Ala168Asn, +, Tyr171AsnGly162Asp, +, Gly165Ser, +, Ala168AsnGly162Pro, +, Asn163Gln, +, Tyr171ValAsn166Glu, +, Ala168Ser, +, Asn170GlnThr167Pro, +, Pro169Ser, +, Tyr171HisGly162Gln, +, Asn163Gln, +, Gly165AspAla164Ser, +, Thr167Ser, +, Ala168GluThr167Gln, +, Pro169Glu, +, Asn170GlnAsn163Gln, +, Pro169Asn, +, Asn170GlnGly162Glu, +, Ala168Gln, +, Asn170GlnAla164Gly, +, Gly165Ser, +, Asn166AspAla164Ser, +, Ala168Gly, +, Asn170GlnAsn163Glu, +, Ala164Asn, +, Ala168SerThr167Ser, +, Pro169Glu, +, Tyr171SerAla168Glu, +, Pro169Gln, +, Tyr171IleGly162Pro, +, Ala164Pro, +, Tyr171ProGly162Pro, +, Asn166Ser, +, Pro169GluAla164Gly, +, Ala168Asn, +, Tyr171SerAla164Thr, +, Asn170Asp, +, Tyr171LeuAsn163Gln, +, Thr167Glu, +, Pro169SerAsn166Asp, +, Ala168Gln, +, Tyr171ProGly162Asn, +, Ala164Glu, +, Tyr171AlaAsn166Glu, +, Thr167Gln, +, Ala168ProAla164Pro, +, Ala168Gln, +, Asn170AspAla164Thr, +, Gly165Gln, +, Ala168AspAla164Ser, +, Ala168Gly, +, Asn170GluAla164His, +, Gly165Glu, +, Tyr171MetAla164Gln, +, Gly165Asp, +, Asn166GlnGly162Gln, +, Thr167Asn, +, Ala168AsnAla168His, +, Pro169Gln, +, Tyr171GluAla164Gln, +, Asn166Gln, +, Tyr171ValGly162Pro, +, Ala164Ser, +, Asn170GlnThr167Glu, +, Ala168Gly, +, Asn170SerThr167Ser, +, Pro169Gly, +, Asn170SerAsn163Glu, +, Asn166Ser, +, Ala168SerAsn163Gln, +, Ala168Glu, +, Tyr171AlaThr167Ser, +, Ala168Ser, +, Asn170AspGly165Asp, +, Asn166Glu, +, Tyr171ProAsn163Asp, +, Ala164Asp, +, Thr167SerAla164Asp, +, Gly165Glu, +, Asn166GlnGly162Ser, +, Ala164Glu, +, Gly165AspGly165Asn, +, Asn170Glu, +, Tyr171GluGly165Pro, +, Asn170Glu, +, Tyr171Glu
Table 17
ring 4-four sudden change variant Ala164Asn, +, Asn166Asp, +, Thr167Asn, +, Ala168GlnGly162Asn, +, Asn163Gln, +, Ala164Asn, +, Asn170GluAla164Thr, +, Asn166Ser, +, Ala168Asn, +, Pro169GluAla164Gln, +, Pro169Asn, +, Asn170Glu, +, Tyr171ThrAsn163Ser, +, Ala164Thr, +, Thr167Asp, +, Tyr171ThrThr167Ser, +, Pro169Ser, +, Asn170Asp, +, Tyr171SerGly162Asn, +, Thr167Gly, +, Pro169Gln, +, Tyr171SerGly162Pro, +, Asn163Ser, +, Ala168Glu, +, Tyr171ValAsn163Gln, +, Ala168Asp, +, Pro169Gln, +, Asn170GlnAla164Asn, +, Gly165Ser, +, Pro169Gln, +, Tyr171IleGly162Glu, +, Thr167Gln, +, Ala168Ser, +, Tyr171SerGly165Ser, +, Ala168Gly, +, Asn170Asp, +, Tyr171LeuAla164His, +, Gly165Asp, +, Asn166Gln, +, Tyr171ThrAsn163Gln, +, Ala164Ser, +, Asn166Ser, +, Ala168GluAsn166Asp, +, Thr167Asn, +, Asn170Ser, +, Tyr171ThrGly162Asp, +, Gly165Gln, +, Asn170Ser, +, Tyr171GlnGly162Pro, +, Ala168Asn, +, Pro169Glu, +, Tyr171GlyAsn166Gln, +, Thr167Gln, +, Ala168Thr, +, Asn170AspAsn163Gln, +, Thr167Asp, +, Ala168Ser, +, Tyr171ProAla164Pro, +, Thr167Glu, +, Pro169Ser, +, Tyr171ValGly165Asn, +, Asn166Gln, +, Pro169Gly, +, Asn170AspAsn166Ser, +, Thr167Pro, +, Ala168Asn, +, Asn170GluAla164Gly, +, Ala168Asn, +, Pro169Asp, +, Tyr171AlaAla164Gln, +, Gly165Gln, +, Thr167Ser, +, Pro169GluAsn163Glu, +, Gly165Ser, +, Thr167Gln, +, Ala168ThrGly162Pro, +, Ala164Thr, +, Thr167Ser, +, Pro169GlnGly162Gln, +, Asn163Glu, +, Gly165Gln, +, Thr167ProAsn163Ser, +, Pro169Gly, +, Asn170Glu, +, Tyr171SerAsn163Gln, +, Gly165Ser, +, Asn170Asp, +, Tyr171LeuAla164His, +, Gly165Pro, +, Pro169Ser, +, Asn170GlnGly162Pro, +, Asn166Gln, +, Ala168Asn, +, Asn170GluAsn163Gln, +, Gly165Pro, +, Thr167Ser, +, Tyr171GlyAsn163Gln, +, Gly165Asn, +, Asn166Ser, +, Tyr171CysAsn163Asp, +, Gly165Pro, +, Asn166Ser, +, Tyr171GlyAla164Pro, +, Thr167Pro, +, Pro169Glu, +, Asn170SerAsn163Asp, +, Ala164Glu, +, Pro169Gln, +, Tyr171HisAsn163Glu, +, Ala164Glu, +, Ala168Gly, +, Tyr171HisThr167Asp, +, Ala168Glu, +, Pro169Gln, +, Asn170SerAla164Asp, +, Gly165Asp, +, Ala168Asn, +, Pro169GlnGly162Ser, +, Ala164Gly, +, Asn170Asp, +, Tyr171GluAsn163Gln, +, Thr167Asn, +, Ala168Asp, +, Pro169GluAsn163Ser, +, Gly165Pro, +, Ala168Asp, +, Pro169GluGly165Ser, +, Ala168Asp, +, Pro169Glu, +, Asn170SerAsn166Gln, +, Ala168Gln, +, Pro169Asp, +, Asn170AspAla164Gly, +, Thr167Gly, +, Pro169Glu, +, Asn170AspGly162Pro, +, Ala164Gly, +, Pro169Asp, +, Asn170GluAla164Pro, +, Thr167Glu, +, Ala168Asp, +, Pro169AspGly162Asp, +, Asn163Gln, +, Ala168His, +, Asn170AspGly162Glu, +, Ala164Ser, +, Asn166Ser, +, Asn170GluGly162Glu, +, Ala164Ser, +, Asn166Gln, +, Asn170GluThr167Asp, +, Ala168His, +, Pro169Glu, +, Tyr171ProAsn163Glu, +, Ala164His, +, Gly165Asp, +, Asn166GlnAsn163Asp, +, Ala164Gln, +, Gly165Asp, +, Asn166SerAsn163Glu, +, Ala164Asp, +, Gly165Gln, +, Ala168AspGly162Glu, +, Ala164Glu, +, Asn166Ser, +, Pro169AspAla164Glu, +, Asn166Asp, +, Asn170Ser, +, Tyr171GlyAla164Glu, +, Gly165Gln, +, Asn166Glu, +, Tyr171CysAla164Asp, +, Asn166Glu, +, Thr167Asn, +, Pro169AsnThr167Asp, +, Pro169Glu, +, Asn170Glu, +, Tyr171SerAsn166Asp, +, Thr167Ser, +, Ala168Asp, +, Tyr171His
Table 18
Ring 5-single mutation varient
Ser191Asp
Ser191Glu
Ser192Asp
Ser192Glu
Phe193Ala
Phe193Asn
Phe193Asp
Phe193Cys
Phe193Gln
Phe193Glu
Phe193Gly
Phe193His
Phe193Ile
Phe193Leu
Phe193Met
Phe193Pro
Phe193Ser
Phe193Thr
Phe193Tyr
Phe193Val
Ser194Asp
Ser194Glu
Thr195Asn
Thr195Asp
Thr195Gln
Thr195Glu
Thr195Gly
Thr195Pro
Thr195Ser
Table 19
the two sudden change of ring 5-variant Ser192Asp, +, Phe193SerSer192Asp, +, Phe193MetSer191Glu, +, Phe193AsnSer191Asp, +, Phe193IleSer191Glu, +, Phe193GlnSer191Asp, +, Thr195SerPhe193Gly, +, Thr195AspSer192Asp, +, Phe193CysSer191Glu, +, Thr195ProSer191Glu, +, Phe193MetPhe193Thr, +, Thr195GluSer192Asp, +, Thr195GlnPhe193Asp, +, Thr195AsnSer191Asp, +, Phe193GlnPhe193Gly, +, Thr195ProSer192Asp, +, Thr195SerSer191Glu, +, Phe193IlePhe193Gln, +, Thr195AsnSer191Glu, +, Thr195GlySer191Glu, +, Phe193HisSer191Asp, +, Phe193LeuSer192Glu, +, Phe193ProPhe193His, +, Thr195GluSer192Asp, +, Thr195GlySer192Glu, +, Phe193AlaSer192Glu, +, Phe193ValSer192Asp, +, Phe193LeuSer192Glu, +, Phe193AsnPhe193Tyr, +, Thr195SerPhe193His, +, Thr195AsnSer192Glu, +, Thr195SerPhe193Ile, +, Thr195GluPhe193Val, +, Thr195AsnPhe193Met, +, Thr195GlnSer191Asp, +, Thr195ProSer192Glu, +, Phe193TyrPhe193Ser, +, Thr195AsnSer192Glu, +, Phe193GlnSer191Asp, +, Phe193SerSer192Asp, +, Phe193IleSer192Asp, +, Phe193HisSer192Asp, +, Phe193GlySer191Glu, +, Phe193SerSer192Glu, +, Thr195GlnSer191Glu, +, Thr195SerSer191Asp, +, Thr195AsnSer191Glu, +, Phe193ValPhe193Tyr, +, Thr195AspPhe193His, +, Thr195SerSer192Glu, +, Phe193IlePhe193Met, +, Thr195GlySer191Glu, +, Phe193TyrSer191Asp, +, Thr195GlnSer192Asp, +, Phe193AsnSer192Asp, +, Phe193ThrSer192Glu, +, Phe193CysPhe193Asp, +, Thr195GlnPhe193Val, +, Thr195GlnSer192Glu, +, Phe193ThrPhe193Leu, +, Thr195Glu
Table 20
ring 5-three sudden change variant Ser192Glu, +, Phe193Thr, +, Thr195GlySer191Glu, +, Phe193His, +, Thr195SerSer192Asp, +, Phe193Leu, +, Thr195AsnSer191Asp, +, Phe193Ala, +, Thr195SerSer192Asp, +, Phe193Val, +, Thr195GlnSer191Asp, +, Phe193Ser, +, Thr195ProSer191Asp, +, Phe193Ile, +, Thr195GlySer192Glu, +, Phe193His, +, Thr195GlySer192Glu, +, Phe193Leu, +, Thr195AsnSer192Asp, +, Phe193Gly, +, Thr195GlnSer192Asp, +, Phe193Ile, +, Thr195ProSer191Glu, +, Phe193Asn, +, Thr195SerSer192Asp, +, Phe193Met, +, Thr195AsnSer191Glu, +, Phe193Gly, +, Thr195AsnSer192Glu, +, Phe193His, +, Thr195AsnSer192Asp, +, Phe193Met, +, Thr195ProSer191Glu, +, Phe193Leu, +, Thr195AsnSer191Glu, +, Phe193Met, +, Thr195AsnSer192Glu, +, Phe193Ala, +, Thr195GlnSer191Glu, +, Phe193Tyr, +, Thr195GlySer192Asp, +, Phe193Ala, +, Thr195GlySer191Glu, +, Phe193Met, +, Thr195GlySer192Glu, +, Phe193Thr, +, Thr195GlnSer191Asp, +, Phe193Asn, +, Thr195GlySer192Glu, +, Phe193Asn, +, Thr195SerSer192Asp, +, Phe193Ser, +, Thr195GlySer192Glu, +, Phe193Leu, +, Thr195ProSer191Asp, +, Phe193Cys, +, Thr195GlySer191Asp, +, Ser192Asp, +, Phe193TyrSer191Asp, +, Ser192Asp, +, Phe193GlySer191Asp, +, Ser192Glu, +, Phe193MetSer191Asp, +, Ser192Glu, +, Thr195GlnSer191Glu, +, Ser192Asp, +, Phe193ValSer191Glu, +, Ser192Glu, +, Phe193ThrSer191Glu, +, Ser192Asp, +, Phe193ThrSer191Asp, +, Ser192Asp, +, Thr195GlySer191Glu, +, Ser192Glu, +, Phe193AsnSer191Asp, +, Ser192Glu, +, Phe193AlaSer191Asp, +, Ser192Asp, +, Phe193AsnSer191Asp, +, Ser192Asp, +, Phe193ProSer191Asp, +, Ser192Glu, +, Phe193ThrSer191Asp, +, Ser192Asp, +, Thr195AsnSer191Asp, +, Ser192Asp, +, Thr195GlnSer191Glu, +, Ser192Asp, +, Phe193AsnSer191Glu, +, Ser192Glu, +, Phe193GlnSer191Glu, +, Ser192Asp, +, Phe193LeuSer191Asp, +, Ser192Asp, +, Thr195SerSer191Asp, +, Ser192Glu, +, Phe193SerSer191Glu, +, Ser192Asp, +, Phe193TyrSer191Asp, +, Ser192Asp, +, Phe193ThrSer191Asp, +, Ser192Glu, +, Phe193ProSer191Glu, +, Ser192Asp, +, Phe193IleSer191Asp, +, Ser192Glu, +, Phe193TyrSer191Glu, +, Ser192Glu, +, Phe193TyrSer191Asp, +, Ser192Asp, +, Phe193SerSer191Glu, +, Ser192Glu, +, Thr195ProSer191Asp, +, Ser192Glu, +, Thr195SerSer191Glu, +, Ser192Asp, +, Phe193MetSer191Asp, +, Ser192Glu, +, Thr195ProSer191Glu, +, Ser192Asp, +, Phe193His
Table 21
ring 5-four sudden change variant Ser191Asp, +, Ser192Glu, +, Phe193Gly, +, Thr195GlnSer191Glu, +, Ser192Asp, +, Phe193His, +, Thr195GlySer191Glu, +, Ser192Glu, +, Phe193Cys, +, Thr195ProSer191Asp, +, Ser192Glu, +, Phe193Cys, +, Thr195GlnSer191Asp, +, Ser192Glu, +, Phe193Thr, +, Thr195ProSer191Glu, +, Ser192Glu, +, Phe193Val, +, Thr195AsnSer191Asp, +, Ser192Glu, +, Phe193Val, +, Thr195AsnSer191Glu, +, Ser192Glu, +, Phe193Leu, +, Thr195SerSer191Glu, +, Ser192Asp, +, Phe193Cys, +, Thr195GlnSer191Glu, +, Ser192Asp, +, Phe193Pro, +, Thr195ProSer191Glu, +, Ser192Asp, +, Phe193Ser, +, Thr195GlySer191Glu, +, Ser192Asp, +, Phe193Pro, +, Thr195AsnSer191Glu, +, Ser192Glu, +, Phe193Ser, +, Thr195ProSer191Glu, +, Ser192Asp, +, Phe193Ala, +, Thr195GlySer191Asp, +, Ser192Glu, +, Phe193His, +, Thr195AsnSer191Asp, +, Ser192Glu, +, Phe193Asn, +, Thr195AsnSer191Glu, +, Ser192Glu, +, Phe193Gln, +, Thr195SerSer191Glu, +, Ser192Glu, +, Phe193Thr, +, Thr195GlnSer191Glu, +, Ser192Glu, +, Phe193Asn, +, Thr195GlnSer191Glu, +, Ser192Glu, +, Phe193Tyr, +, Thr195SerSer191Asp, +, Ser192Glu, +, Phe193Ile, +, Thr195ProSer191Glu, +, Ser192Asp, +, Phe193Val, +, Thr195GlnSer191Glu, +, Ser192Asp, +, Phe193Val, +, Thr195AsnSer191Asp, +, Ser192Glu, +, Phe193Tyr, +, Thr195SerSer191Asp, +, Ser192Glu, +, Phe193Ala, +, Thr195SerSer191Glu, +, Ser192Glu, +, Phe193His, +, Thr195AsnSer191Asp, +, Ser192Asp, +, Phe193Pro, +, Thr195AsnSer191Asp, +, Ser192Asp, +, Phe193Gln, +, Thr195SerSer191Asp, +, Ser192Asp, +, Phe193Leu, +, Thr195AsnSer191Asp, +, Ser192Glu, +, Phe193Val, +, Thr195GlnSer191Glu, +, Ser192Glu, +, Phe193Gly, +, Thr195GlySer191Glu, +, Ser192Glu, +, Phe193Thr, +, Thr195ProSer191Glu, +, Ser192Glu, +, Phe193Thr, +, Thr195GlySer191Glu, +, Ser192Asp, +, Phe193Ile, +, Thr195SerSer191Glu, +, Ser192Glu, +, Phe193Ile, +, Thr195GlySer191Asp, +, Ser192Asp, +, Phe193Pro, +, Thr195ProSer191Asp, +, Ser192Asp, +, Phe193Ile, +, Thr195GlySer191Glu, +, Ser192Asp, +, Phe193Thr, +, Thr195GlySer191Asp, +, Ser192Glu, +, Phe193Ser, +, Thr195GlySer191Glu, +, Ser192Asp, +, Phe193Tyr, +, Thr195SerSer191Asp, +, Ser192Asp, +, Phe193Thr, +, Thr195GlnSer191Asp, +, Ser192Glu, +, Phe193Ser, +, Thr195GlnSer191Glu, +, Ser192Glu, +, Phe193His, +, Thr195SerSer191Glu, +, Ser192Asp, +, Phe193Leu, +, Thr195AsnSer191Asp, +, Ser192Glu, +, Phe193Leu, +, Thr195ProSer191Asp, +, Ser192Asp, +, Phe193Ile, +, Thr195ProSer191Asp, +, Ser192Asp, +, Phe193Tyr, +, Thr195SerSer191Asp, +, Ser192Glu, +, Phe193Ile, +, Thr195GlnSer191Asp, +, Ser192Glu, +, Phe193Pro, +, Thr195SerSer191Asp, +, Ser192Glu, +, Phe193Leu, +, Thr195GlnSer191Glu, +, Ser192Asp, +, Phe193Asn, +, Thr195SerSer191Glu, +, Ser192Glu, +, Phe193Ser, +, Thr195AsnSer191Asp, +, Ser192Asp, +, Phe193Glu, +, Thr195GlnSer191Asp, +, Ser192Glu, +, Phe193Glu, +, Thr195ProSer191Glu, +, Ser192Asp, +, Phe193Glu, +, Thr195GlnSerl91Glu, +, Ser192Glu, +, Phe193Glu, +, Thr195GlySer191Glu, +, Ser192Glu, +, Phe193Asp, +, Thr195GlySer191Asp, +, Ser192Asp, +, Phe193Glu, +, Thr195SerSer191Glu, +, Ser192Asp, +, Phe193Asp, +, Thr195ProSer191Glu, +, Ser192Glu, +, Phe193Asp, +, Thr195Gln
Table 22
Ring 6-single mutation varient
Ala204Asn
Ala204Asp
Ala204Gln
Ala204Glu
Ala204Gly
Ala204His
Ala204Pro
Ala204Ser
Ala204Thr
Pro205Asn
Pro205Asp
Pro205Gln
Pro205Glu
Pro205Gly
Pro205Ser
Gly206Asn
Gly206Asp
Gly206Gln
Gly206Glu
Gly206Pro
Gly206Ser
Ser207Asp
Ser207Glu
Trp208Ala
Trp208Asn
Trp208Asp
Trp208Cys
Trp208Gln
Trp208Glu
Trp208Gly
Trp208His
Trp208Ile
Trp208Leu
Trp208Met
Trp208Phe
Trp208Pro
Trp208Ser
Trp208Thr
Trp208Tyr
Trp208Val
Ile209Ala
Ile209Asn
Ile209Asp
Ile209Cys
Ile209Gln
Ile209Glu
Ile209Gly
Ile209His
Ile209Leu
Ile209Met
Ile209Pro
Ile209Ser
Ile209Thr
Ile209Val
Tyr210Ala
Tyr210Asn
Tyr210Asp
Tyr210Cys
Tyr210Gln
Tyr210Glu
Tyr210Gly
Tyr210His
Tyr210Ile
Tyr210Leu
Tyr210Met
Tyr210Pro
Tyr210Ser
Tyr210Thr
Tyr210Val
Ser211Asp
Ser211Glu
Thr212Asn
Thr212Asp
Thr212Gln
Thr212Glu
Thr212Gly
Thr212Pro
Thr212Ser
Tyr213Ala
Tyr213Asn
Tyr213Asp
Tyr213Cys
Tyr213Gln
Tyr213Glu
Tyr213Gly
Tyr213His
Tyr213Ile
Tyr213Leu
Tyr213Met
Tyr213Pro
Tyr213Ser
Tyr213Thr
Tyr213Val
Pro214Asn
Pro214Asp
Pro214Gln
Pro214Glu
Pro214Gly
Pro214Ser
Thr215Asn
Thr215Asp
Thr215Gln
Thr215Glu
Thr215Gly
Thr215Pro
Thr215Ser
Ser216Asp
Ser216Glu
Thr217Asn
Thr217Asp
Thr217Gln
Thr217Glu
Thr217Gly
Thr217Pro
Thr217Ser
Tyr218Ala
Tyr218Asn
Tyr218Asp
Tyr218Cys
Tyr218Gln
Tyr218Glu
Tyr218Gly
Tyr218His
Tyr218Ile
Tyr218Leu
Tyr218Met
Tyr218Pro
Tyr218Ser
Tyr218Thr
Tyr218Val
Ala219Asn
Ala219Asp
Ala219Gln
Ala219Glu
Ala219Gly
Ala219His
Ala219Pro
Ala219Ser
Ala219Thr
Ser220Asp
Ser220Glu
Leu221Ala
Leu221Asn
Leu221Asp
Leu221Cys
Leu221Gln
Leu221Glu
Leu221Gly
Leu221His
Leu221Ile
Leu221Met
Leu221Pro
Leu221Ser
Leu221Thr
Leu221Val
Ser222Asp
Ser222Glu
Gly223Asn
Gly223Asp
Gly223Gln
Gly223Glu
Gly223Pro
Gly223Ser
Thr224Asn
Thr224Asp
Thr224Gln
Thr224Glu
Thr224Gly
Thr224Pro
Thr224Ser
Direction will be connected at a distance of two-way with negative electrode plate or the unidirectional conducting of the positive electrode plate of d> = 0 respectively.The positive electrode plate of induced electromotive force power supply and induced charge generation electric organ and the length of negative electrode plate or width or thickness are than the positive electrode plate of permanent electric field and negative electrode plate is little or equate greatly or preferably. induced electric field induced charge generator of the positive electrode plate and a negative electrode plate in the longitudinal direction or the width direction of the One end or both ends, respectively, of the induced electric field and the induced electromotive force power generator of the charge generating positive electrode plate and the negative electrode plates parallel to the coincident or parallel connection or docking coincident or conduction or induction field is formed integrally induced charge generator The positive electrode plate negatively charged plate inside the plane and the induced electromotive force power and charge generating generators positive electrode plate inside the plane were negative electrode plate inside the power supply and induced charge flow is unidirectional conducting positive electrode plate close to the negative electrode plate lateral conduction Connect or made into one. Be be positioned between the permanent electric field positive electrode any solid of any solid negative electrode or the parallel metal conductor utmost point inner or inside and outside can be respectively under the induction of permanent electric field, induce induced positive and induction negative electrical charge, can be from the conical surface metallic conductor tip of positive electrode plate and negative electrode plate or the wedge metal conductor tip escape the emission induced charge and the negative electrical charge of inducting automatically present rectangle or the taper of single head single face or single head single face wedge shape or two-sided taper of single head or the two-sided wedge shape of single head with parallel with negative electrode plate or the uneven cross section of permanent electric field positive electrode plate respectively, or single head single face needle point shape or single head two-sided needle point shape or the taper of double end single face or the two-sided wedge shape of double end or the two-sided needle point shape of double end or how much conductors of the two-sided taper of double end or any geometry be to solid or a pair of not parallel or parallel metal conductor plate, a termination or the two ends of long with the positive electrode plate of induction field charge inducing the generator respectively or cross direction of one or two positive electrode plate of induced electromotive force power supply and induced charge generation electric organ and one or two negative electrode plate and negative electrode plate is long or a termination of cross direction or parallel coincidences of two ends dock to be connected and lead or make one.The taper of positive electrode plate and negative electrode plate, wedge shape, needle point shape single face angle opposite face towards or opposing towards or the center symmetry towards, or the axle center symmetry towards, the taper of positive electrode plate and negative electrode plate, wedge shape pin, pointed two-sided angle, opposite face towards or opposing towards or the axle center symmetry towards, or the center symmetry is filled dielectric or is not filled dielectric except that the passage of reserving the most advanced and sophisticated emission travel path of escaping of induced charge metallic conductor towards, two parallel-plate outsides.Two relative parallel planes of positive electrode plate and negative electrode plate are close to fully mutually that conducting is connected or at a distance of spacing d> = 0, the positive electrode plate of induced electromotive force power supply and induced charge generation electric organ and negative electrode plate respectively the length overall of the positive electrode plate with the charge inducing generator after butt joint is connected conducting or makes one with negative electrode plate, beam overall, total thickness can be respectively than permanent electric field positive electrode plate and the permanent length and width of electric field negative electrode plate and thick either large or small or equal.EEBG01-EEBG02-EEBG03-EEBG04-EEBG05-EEBG06-EEBG07-EEBG08-EEBG09-EEBG10-EEBG11-EEBG12-EEBG13 -EEBG14-EEBG15-EEBG16-EEBG17-EEBG18-EEBG19-EEBG20-HHBG01-HHBG02-HHBG03-HHBG04 permanent induction electromagnetic field change-section conductor charge automatic escape emission power generator, characteristics of principle and shape structure general technical feature at first be to use permanent electric field, the secondth, the electromagnetic field inducing of the permanent electric field of application, the 3rd is that the application permanent electro magnetic field is that the mobile device of the inner unidirectional conducting of charge inducing generator and charge inducing power supply produces the principle that electromagnetic induction is isolated positive and negative charge inducing afterwards to the metallic conductor that is arranged in the permanent electric field, the 4th be make to adopt variable-section variable dimension awl wedge shape list or double end list double inclined plane does not wait or etc. gradient metallic conductor tip be induced electromotive force power supply and induced charge generation electric organ, escape and launch charge theory in the tip of induced charge escape reflector, the 5th is to use the charging photocell or friction produces electricity battery, charging capacitor, the moving forever power supply of charging environment friendly, the charge switch power-off switch, the moving forever amplifying type charger of forming of the moving forever permanent electric field of power supply waits and guarantees moving forever continuously output induced charge of moving forever power supply and electric energy energy.The induced electromotive force ε of induced electromotive force power supply and induced charge generation electric organ ...
42Thr212Gln?+?Ala219GluAla204Gly?+?Trp208GlnAla204Thr?+?Ser216AspThr212Gln?+?Tyr218GlnSer207Glu?+?Leu221MetThr215Pro?+?Gly223GlnAla204Gly?+?Ser216AspTyr210Asp?+?Ala219HisIle209Gln?+?Tyr218AlaIle209Ala?+?Ala219ProAla204Asn?+?Ser222GluTyr210Asp?+?Tyr213AlaTyr218Leu?+?Thr224GluTyr218Asn?+?Ser220GluTrp208Met?+?Ala219ProPro205Gly?+?Ser222AspLeu221Val?+?Thr224GlnTrp208Ile?+?Pro214SerTrp208Asp?+?Thr212ProAla204Thr?+?Gly223GlnThr217Gln?+?Tyr218IleTyr213His?+?Ser216AspThr212Ser?+?Thr215AspThr217Asn?+?Leu221AsnPro214Asp?+?Thr217ProSer207Glu?+?Ala219HisThr217Asp?+?Tyr218HisTrp208Ala?+?Thr217SerPro205Gln?+?Ser220AspIle209Gly?+?Ser216GluTyr218Ser?+?Ser220GluThr215Asn?+?Ser216GluThr215Gly?+?Tyr218GlnThr217Ser?+?Leu221AlaAla219Pro?+?Leu221HisPro205Gln?+?Leu221MetTyr213Met?+?Leu221IleTrp208Asn?+?Thr212SerSer207Glu?+?Thr224GlyPro205Ser?+?Leu221CysAla204Gly?+?Tyr210ValTrp208Phe?+?Ser222AspIle209Thr?+?Ser222GluLeu221Ile?+?Ser222GluTyr213Pro?+?Thr217GluIle209Thr?+?Ser216GluTyr210Cys?+?Ser222AspLeu221Glu?+?Thr224SerTyr213Ala?+?Thr217ProTrp208Cys?+?Thr215GluAla204Ser?+?Thr217SerIle209His?+?Gly223SerAla204Asn?+?Trp208Tyr
43Pro205Gln?+?Ser207GluAla204Asn?+?Trp208MetTyr210Pro?+?Leu221AspTyr210Gln?+?Thr215SerAla204Pro?+?Ser216GluAla204Gly?+?Ser222AspSer216Asp?+?Leu221MetTyr210Ile?+?Ala219AsnPro214Glu?+?Thr224SerPro205Gln?+?Thr215SerAla204Gly?+?Pro205AsnTyr210Asp?+?Tyr218ValTrp208Ser?+?Thr215GlySer222Glu?+?Thr224SerTrp208Gln?+?Ser216AspSer207Asp?+?Gly223SerPro205Gly?+?Tyr210CysThr212Gly?+?Thr224AspSer220Glu?+?Gly223ProGly206Pro?+?Tyr210MetTyr210Ser?+?Ser222AspSer207Glu?+?Pro214GlnPro205Gly?+?Gly223AsnTyr213Ser?+?Pro214AspPro214Gln?+?Ser220AspAla204Thr?+?Ser222GluAla219Asn?+?Leu221AspGly206Ser?+?Thr215ProThr212Asn?+?Tyr218ValThr217Pro?+?Gly223AspGly206Pro?+?Tyr218AsnGly206Gln?+?Thr217AspTyr210Ala?+?Ser220AspPro214Asp?+?Tyr218ValLeu221His?+?Gly223AspPro214Gln?+?Gly223AspIle209Pro?+?Ser216AspIle209Thr?+?Gly223AspPro214Asn?+?Ala219AspTyr218Cys?+?Ser220GluSer207Glu?+?Tyr218AsnTyr218Gly?+?Leu221GlnIle209Thr?+?Tyr218ValPro214Glu?+?Gly223SerTyr213Met?+?Ala219ThrSer222Glu?+?Thr224AsnTrp208Asp?+?Ile209MetThr212Gln?+?Pro214GlnSer207Asp?+?Tyr213LeuThr212Gln?+?Gly223ProTyr210Leu?+?Ser216GluSer216Asp?+?Ala219ThrTyr213Gln?+?Thr217AspGly206Pro?+?Ser222GluAla204Thr?+?Ser220AspAla219Thr?+?Thr224ProTrp208Ile?+?Ala219GluIle209Gly?+?Thr215SerGly206Gln?+?Tyr210GluPro214Gln?+?Ser220GluSer207Glu?+?Thr217AsnAla204Pro?+?Gly223AspIle209Cys?+?Ser222AspPro214Gly?+?Gly223ProIle209Met?+?Thr224ProPro214Glu?+?Thr217SerPro205Ser?+?Ser207AspTyr210Thr?+?Thr212GlnGly206Gln?+?Tyr218ProTyr218Val?+?Ser222GluLeu221Asn?+?Gly223GluPro205Gln?+?Tyr218ValPro205Gln?+?Thr217AsnTrp208His?+?Ile209AlaPro205Ser?+?Gly223GlnPro214Ser?+?Thr217GlyTyr218His?+?Ser222AspThr212Gln?+?Gly223SerThr215Glu?+?Ala219ThrTyr213Gly?+?Tyr218AspThr212Gln?+?Tyr213GlnTyr210Ile?+?Thr215AspAla204Asn?+?Gly223ProSer207Glu?+?Ile209AsnThr215Gln?+?Ala219AspSer220Asp?+?Gly223ProPro205Ser?+?Tyr213AlaTrp208Gly?+?Ser222GluThr215Glu?+?Tyr218AlaAla204Gln?+?Ala219GlnPro205Asn?+?Tyr213ThrTyr218Thr?+?Thr224GlnSer222Asp?+?Thr224SerAla204Pro?+?Tyr213CysGly206Gln?+?Leu221GlySer216Glu?+?Thr224SerSer207Asp?+?Ala219AsnTrp208Leu?+?Ile209HisPro205Ser?+?Tyr213ValThr212Gly?+?Thr215Asp
Table 24
Ring 6 - three mutant Gly206Ser + Thr212Ser + Ala219GluAla204Asn + Thr212Ser + Ser216GluPro205Gln + Leu221Glu + Gly223AsnTrp208Thr + Ile209Cys + Thr224AspIle209Met + Thr212Gln + Ser220AspTyr210Gly + Tyr213Gly + Thr224GlySer207Glu + Tyr210Ser + Gly223AsnTyr213Gly + Ser216Asp + Thr217SerPro205Asn + Ser216Glu + Thr224AsnThr215Glu + Ala219Gln + Leu221ThrAla204Asn + Thr217Asn + Tyr218GluThr212Ser + Thr217Gly + Thr224GlnAla204Ser + Tyr218His + Ala219GlnPro205Ser + Tyr213Ser + Leu221AsnAla204Ser + Gly206Ser + Ala219SerAla204Gly + Trp208Gln + Ser216AspSer207Glu + Tyr218Gln + Leu221MetAla204Gly + Thr215Pro + Gly223GlnIle209Gln + Tyr218Ala + Ala219ProAla204Asn + Trp208Met + Ser222GluTrp208Met + Ala219Pro + Ser222AspPro205Gly + Leu221Val + Thr224GlnAla204Thr + Thr212Pro + Gly223GlnGly206Gln + Ile209Gln + Thr212GlnGly206Pro + Ser220Glu + Leu221SerGly206Gln + Tyr210Gly + Ser222AspAla204Gly + Tyr213Thr + Pro214GlnAla204His + Thr212Gln + Thr224GlnGly206Gln + Pro214Asp + Tyr218SerThr212Asn + Ser216Asp + Thr217SerSer207Asp + Tyr213Ile + Thr224ProPro205Gln + Tyr213Met + Leu221HisTrp208Asn + Thr212Ser + Gly223AspSer207Glu + Leu221Gly + Thr224GlyPro205Ser + Tyr210Val + Leu221CysPro205Gly + Ile209His + Tyr213ThrIle209Pro + Tyr210Asn + Ser220AspPro205Gly + Thr212Pro + Thr224GlyTrp208Cys + Thr217Asp + Ala219AsnPro205Gly + Leu221Cys + Gly223ProAla204His + Ser216Glu + Leu221SerThr217Asp + Gly223Ser + Thr224GlyPro205Gln + Trp208Gln + Ile209AlaThr212Gly + Thr217Gly + Leu221HisGly206Asn + Thr212Gly + Tyr213GlyGly206Asn + Ser207Glu + Thr212SerThr212Gln + Leu221Glu + Gly223SerTyr210His + Thr215Asp + Thr224ProPro214Gln + Thr215Pro + Ser216GluPro205Gly + Tyr213Val + Gly223AspTrp208Phe + Thr215Asn + Thr224GlyTyr213Met + Ala219Pro + Ser220GluTrp208Phe + Ile209Ser + Tyr213GlnGly206Ser + Ser216Glu + Tyr218ProAla204Gln + Tyr210His + Thr224GluPro205Ser + Thr212Pro + Ala219SerPro205Gln + Tyr210Met + Thr217ProAla204Gly + Ile209His + Ser216GluThr212Asn + Thr217Ser + Thr224AsnGly206Pro + Tyr210Gly + Gly223GlnPro205Gln + Thr217Asp + Ala219ThrPro205Ser + Ile209Met + Ser216AspThr215Asn + Ser216Glu + Thr224SerPro205Gln + Leu22lThr + Ser222GluTyr210Cys + Ala219Asn + Leu221ThrAla204Ser + Gly206Ser + Ala219GlnIle209Pro + Ser216Asp + Leu221CysTrp208Thr + Tyr210Val + Thr212SerThr212Gly + Pro214Asp + Gly223GlnPro214Gln + Thr215Ser + Thr224GluThr212Ser + Pro214Gln + Leu221HisTrp208Gly + Ser220Glu + Gly223SerPro205Ser + Ser220Asp + Leu221ThrGly206Asn + Thr215Pro + Leu221AlaTyr213Leu + Leu221His + Gly223AspSer207Asp + Thr212Gly + Tyr218CysGly206Gln + Ile209Val + Ala219ThrTrp208Ile + Tyr218Ile + Gly223AsnAla204His + Ile209Gly + Ser216AspTrp208Leu + Thr212Gly + Ala219SerThr212Gln + Pro214Glu + Ala219ThrPro205Gln + Ser207Asp + Thr212ProPro205Ser + Tyr210Pro + Tyr218IleLeu221Ala + Gly223Asn + Thr224GluAla204Thr + Gly206Gln + Ser207AspSer216Glu + Ala219Gln + Gly223GlnPro205Gly + Trp208Leu + Leu221GlnThr217Gln + Gly223Gln + Thr224GluThr212Gly + Thr217Ser + Tyr218AlaGly206Asn + Gly223Asp + Thr224AsnAla204Gly + Tyr210Cys + Tyr213ThrGly206Ser + Thr212Asn + Thr215GlyAla204Asn + Thr212Asn + Ser216GluGly206Gln + Tyr218Cys + Gly223GluAla204Ser + Pro205Ser + Gly206AsnIle209Gly + Leu221Val + Thr224ProGly206Asn + Trp208His + Thr217GlyGly206Ser + Trp208Leu + Ser222AspPro205Gly + Thr212Gln + Ser222AspAla204Thr + Tyr213Gln + Thr224ProThr212Ser + Thr217Ser + Gly223AspPro205Ser + Tyr213Ile + Ser222GluIle209Pro + Tyr210Asp + Ala219ProGly206Gln + Thr215Pro + Ser220GluTrp208Cys + Tyr210Leu + Thr215GlyTrp208Tyr + Thr212Gln + Ser222GluGly206Asn + Ser222Asp + Gly223AsnPro205Gly + Gly206Asn + Leu221CysPro205Gln + Tyr213Ile + Ser216GluAla204His + Tyr210His + Ser220AspAla204Thr + Thr212Asn + Ala219AspSer207Glu + Tyr210Ala + Thr212GlyTyr210His + Thr217Gly + Leu221MetAla204Thr + Ile209Met + Ser222GluTrp208Pro + Ala219Pro + Ser222AspAla204His + Ile209Ser + Ser220GluPro214Ser + Leu221Glu + Gly223GlnGly206Pro + Leu221Met + Gly223AspAla204His + Tyr213Thr + Ser222AspTyr213Ala + Leu221Met + Ser222AspTrp208Leu + Thr212Ser + Pro214AspTyr213Ile + Ser216Glu + Thr217ProPro205Gln + Pro214Gln + Thr224GlyTyr213Cys + Thr217Gly + Ser220GluGly206Asn + Thr212Gly + Tyr218ProGly206Pro + Ser216Glu + Gly223ProThr212Gln + Thr215Gly + Ser222GluAla204Pro + Thr217Asp + Thr224SerPro205Ser + Thr212Pro + Ala219AspIle209Cys + Pro214Ser + Thr215AspIle209Cys + Ser220Asp + Gly223GlnThr217Gly + Ser220Asp + Leu221GlnAla204His + Pro205Asn + Trp208GluAla204Gln + Thr212Ser + Thr215AspPro214Asn + Ser220Glu + Leu221GlyIle209Gly + Thr215Asn + Ala219ProSer207Glu + Thr217Gln + Thr224SerAla204Gly + Thr215Asn + Gly223ProIle209Ser + Tyr213Ile + Leu221MetTyr210Thr + Pro214Ser + Ser222AspTyr210Leu + Thr212Ser + Leu221AsnGly206Asn + Pro214Asp + Tyr218MetGly206Asn + Pro214Gln + Ala219AsnSer207Glu + Pro214Ser + Ala219HisAla204Asn + Trp208Ala + Ile209GlnThr217Glu + Tyr218Leu + Gly223AsnTrp208Pro + Pro214Gly + Leu221AlaGly206Pro + Thr215Ser + Leu221CysAla204Ser + Ile209Val + Thr224AspTrp208Ile + Tyr210Pro + Thr224AspThr212Gln + Thr215Asn + Thr217AspTyr210Ser + Tyr213Cys + Thr217AsnThr212Gln + Ser222Asp + Gly223GlnTyr210Asn + Thr217Glu + Tyr218MetPro214Asn + Ala219Gln + Ser220GluPro205Ser + Trp208Met + Leu221AspAla204Asn + Tyr210Cys + Tyr213AsnTyr218Leu + Leu221His + Ser222GluAla204His + Tyr218Ser + Ser222AspGly206Pro + Tyr213Asn + Pro214AsnGly206Pro + Thr215Gln + Tyr218SerAla204Pro + Ile209His + Leu221ThrGly206Gln + Thr212Gly + Gly223GluThr215Gly + Tyr218Ala + Thr224ProPro205Gln + Tyr213Gly + Gly223GluAla204Gly + Tyr213Asn + Leu221ThrTrp208Gly + Ile209His + Thr215SerAla204His + Ser207Glu + Tyr213CysTrp208His + Tyr210His + Ser222AspPro205Gly + Tyr210Asp + Leu221GlnPro205Asn + Tyr210Ala + Pro214SerThr212Pro + Thr215Gln + Thr224AspAla204Thr + Tyr213Val + Pro214GluAla204Gly + Tyr210Pro + Pro214GluPro205Gly + Trp208His + Tyr218GlyGly206Ser + Ala219Gln + Gly223SerTyr213Thr + Tyr218Cys + Ser220GluThr215Pro + Ser216Glu + Leu221AsnPro205Gly + Thr212Asn + Thr224AspPro205Gly + Ser207Asp + Thr212Ser...
Table 25
ring 6-four sudden change variant Gly206Asn, +, Thr215Gln, +, Tyr218Ile, +, Leu221IleTyr210Gly, +, Thr212Gln, +, Tyr213Gly, +, Thr224GlyPro205Gly, +, Gly206Pro, +, Trp208Asn, +, Thr224SerIle209Thr, +, Pro214Asp, +, Thr217Asn, +, Tyr218CysAla204Ser, +, Tyr218His, +, Ala219Gln, +, Leu221AsnAla204Ser, +, Pro205Ser, +, Tyr213Ser, +, Ala219SerAla204Gly, +, Thr212Gln, +, Ser216Asp, +, Gly223SerSer207Glu, +, Thr215Pro, +, Tyr218Gln, +, Leu221MetAla204Gly, +, Ser216Asp, +, Ala219His, +, Gly223GlnIle209Gln, +, Tyr210Asp, +, Tyr218Ala, +, Ala219ProTrp208Met, +, Tyr218Leu, +, Ala219Pro, +, Ser222GluPro205Gly, +, Leu221Val, +, Ser222Asp, +, Thr224GlnAla204Thr, +, Thr212Pro, +, Ser222Glu, +, Gly223GlnGly206Gln, +, Ile209Gln, +, Thr212Gln, +, Leu221HisAla204Ser, +, Gly206Pro, +, Ser220Asp, +, Leu221SerAla204Gly, +, Thr212Gln, +, Tyr213Thr, +, Thr224GlnTyr210Ala, +, Pro214Ser, +, Tyr218Val, +, Ser222AspAla204Gln, +, Pro205Ser, +, Gly206Ser, +, Ser222GluTrp208Cys, +, Pro214Gln, +, Ala219Thr, +, Thr224AspAla204Gly, +, Gly206Ser, +, Tyr210Asp, +, Leu221GlyAla204Gln, +, Gly206Asn, +, Tyr210Gln, +, Ala219AspPro205Ser, +, Gly206Pro, +, Ile209Val, +, Tyr213ProGly206Pro, +, Pro214Glu, +, Thr215Pro, +, Leu221MetSer207Asp, +, Trp208Met, +, Tyr218Val, +, Leu221ProTyr210Gly, +, Thr212Pro, +, Pro214Gly, +, Ser222AspGly206Pro, +, Thr212Gln, +, Thr217Ser, +, Ser222AspAla204Pro, +, Trp208Met, +, Ile209Val, +, Ser216GluTrp208Ser, +, Tyr218His, +, Ala219His, +, Gly223Pro
49Ala204Gln?+?Trp208Ala?+?Tyr210Asn?+?Ser222GluGly206Gln?+?Ser220Asp?+?Leu221Ala?+?Thr224SerIle209Gln?+?Thr212Ser?+?Ala219Gln?+?Ser220GluPro205Asn?+?Thr212Gly?+?Tyr218Ala?+?Ser222GluPro205Gln?+?Trp208Cys?+?Tyr213Cys?+?Pro214AspPro205Gly?+?Thr215Gln?+?Thr217Pro?+?Gly223SerAla204His?+?Gly206Pro?+?Ser216Glu?+?Leu221SerSer207Asp?+?Leu221Gly?+?Gly223Gln?+?Thr224AsnTyr210His?+?Thr212Ser?+?Leu221Glu?+?Gly223SerPro205Gly?+?Thr215Asn?+?Gly223Asp?+?Thr224GlyTrp208Phe?+?Tyr213Met?+?Thr215Pro?+?Ser220GluGly206Ser?+?Trp208Phe?+?Ile209Ser?+?Tyr213GlnAla204Gln?+?Pro205Ser?+?Thr212Pro?+?Ala219SerAla204Gly?+?Tyr210Met?+?Ser216Glu?+?Thr217ProGly206Pro?+?Thr212Asn?+?Thr217Gln?+?Thr224AsnPro205Ser?+?Ile209Met?+?Thr215Asn?+?Thr224SerTyr210Thr?+?Thr212Pro?+?Tyr218Asn?+?Ser220GluTrp208Thr?+?Tyr210Val?+?Thr212Ser?+?Leu221CysThr212Gly?+?Pro214Asp?+?Thr215Ser?+?Gly223GlnSer207Glu?+?Thr212Ser?+?Pro214Gln?+?Leu221ProPro205Asn?+?Gly206Gln?+?Ser207Asp?+?Leu221ThrPro205Ser?+?Thr215Pro?+?Ser220Asp?+?Leu221CysGly206Asn?+?Tyr213Leu?+?Leu221Ala?+?Gly223AspSer207Asp?+?Thr212Gly?+?Pro214Asn?+?Thr224AsnAla204Pro?+?Ser207Glu?+?Ile209Val?+?Ala219ThrGly206Gln?+?Trp208Ile?+?Tyr218Ile?+?Gly223AsnAla204His?+?Trp208Leu?+?Ile209Gly?+?Ser216AspAla204Gln?+?Thr212Gly?+?Pro214Glu?+?Ala219SerAla204Asn?+?Pro205Gln?+?Ser207Asp?+?Thr212ProPro205Gly?+?Trp208Leu?+?Ser216Glu?+?Ala219GlnTrp208Tyr?+?Thr217Gln?+?Leu221Gln?+?Thr224GluThr212Gly?+?Thr217Ser?+?Tyr218Ala?+?Gly223AspAla204Gly?+?Gly206Asn?+?Thr215Asn?+?Gly223AspGly206Ser?+?Tyr210Cys?+?Tyr213Thr?+?Thr215GlyAla204Gln?+?Pro205Ser?+?Gly206Asn?+?Ala219AspAla204Ser?+?Ile209Gly?+?Leu221Val?+?Thr224ProGly206Asn?+?Ser207Glu?+?Trp208His?+?Thr217GlyGly206Ser?+?Trp208Pro?+?Ala219Thr?+?Ser222AspAla204Thr?+?Tyr213Gln?+?Thr217Ser?+?Thr224ProPro205Ser?+?Thr212Ser?+?Tyr213Ile?+?Gly223AspGly206Gln?+?Ile209Asn?+?Thr215Pro?+?Ser220GluTrp208Cys?+?Thr212Gln?+?Thr215Gly?+?Ser222GluGly206Asn?+?Trp208Tyr?+?Ser222Glu?+?Gly223AsnPro205Gly?+?Gly206Asn?+?Leu221Cys?+?Ser222AspPro205Gln?+?Tyr210His?+?Tyr213Ile?+?Ser220AspAla204His?+?Trp208Asn?+?Thr212Asn?+?Ala219AspAla204His?+?Gly206Pro?+?Leu221Met?+?Gly223AspAla204Ser?+?Tyr213Thr?+?Leu221Met?+?Ser222AspTyr213Ile?+?Pro214Gln?+?Ser216Glu?+?Thr217ProPro205Gln?+?Tyr213Cys?+?Ser220Glu?+?Thr224GlyGly206Asn?+?Tyr213Asn?+?Tyr218Pro?+?Ser220GluPro205Ser?+?Gly206Pro?+?Tyr218Asp?+?Gly223ProAla204Pro?+?Pro205Ser?+?Thr217Asp?+?Thr224SerPro205Asn?+?Trp208Ile?+?Thr212Gln?+?Thr217GlyIle209Cys?+?Pro214Ser?+?Ser220Asp?+?Gly223GlnAla204His?+?Pro205Asn?+?Trp208Glu?+?Tyr210HisIle209Gly?+?Thr215Asn?+?Thr217Asn?+?Ala219ProPro205Gly?+?Pro214Asn?+?Tyr218Ile?+?Ser222AspAla204Ser?+?Pro205Ser?+?Thr212Asn?+?Tyr213IlePro205Gln?+?Ser207Glu?+?Tyr210Pro?+?Thr215SerPro205Gln?+?Ser207Glu?+?Thr212Gln?+?Tyr213SerAla204Ser?+?Ile209Asn?+?Tyr213Cys?+?Ser216AspTrp208Ala?+?Ile209Gln?+?Thr217Glu?+?Gly223AsnTrp208Pro?+?Pro214Gly?+?Tyr218Leu?+?Leu221AlaGly206Pro?+?Thr215Ser?+?Ser216Glu?+?Leu221CysAla204Ser?+?Trp208Ile?+?Ile209Val?+?Thr224AspTyr210Pro?+?Thr212Gln?+?Thr215Asn?+?Thr217AspTyr210Ser?+?Tyr213Cys?+?Pro214Asn?+?Thr217AsnThr212Gln?+?Tyr218Met?+?Ser222Asp?+?Gly223GlnPro205Ser?+?Trp208Met?+?Ala219Gln?+?Leu221AspAla204Asn?+?Tyr210Cys?+?Tyr213Asn?+?Tyr218LeuAla204His?+?Pro205Gly?+?Tyr218Ser?+?Ser222AspGly206Pro?+?Tyr213Asn?+?Pro214Asn?+?Tyr218SerAla204Pro?+?Ile209His?+?Thr215Gln?+?Leu221ThrAla204Asn?+?Gly206Gln?+?Thr212Gly?+?Gly223GluThr215Gly?+?Tyr218Ala?+?Gly223Glu?+?Thr224ProPro205Gln?+?Tyr213Gly?+?Ser220Asp?+?Leu221ThrPro205Gly?+?Trp208His?+?Tyr210His?+?Leu221GlnTyr210Leu?+?Thr212Pro?+?Tyr218Gln?+?Ala219GluGly206Gln?+?Thr212Gln?+?Tyr218His?+?Gly223AspTrp208Ile?+?Tyr213His?+?Thr215Ser?+?Ser222GluTrp208Val?+?Pro214Asn?+?Thr215Gly?+?Leu221AspPro205Asn?+?Tyr213Met?+?Pro214Ser?+?Thr224SerPro205Gly?+?Trp208Met?+?Ile209Leu?+?Tyr213MetPro205Gly?+?Thr217Glu?+?Tyr218Leu?+?Ala219HisTrp208Val?+?Tyr213Gly?+?Ser216Asp?+?Leu221ThrTyr210Gln?+?Thr212Pro?+?Tyr218Gly?+?Gly223GluPro205Gly?+?Trp208Asp?+?Ile209His?+?Tyr210AlaTrp208Ala?+?Ile209Leu?+?Tyr210Glu?+?Tyr213CysGly206Asn?+?Trp208Leu?+?Tyr213Val?+?Ser216AspAla204Pro?+?Pro205Gly?+?Thr217Glu?+?Leu221AlaTrp208Asn?+?Thr212Asn?+?Tyr213His?+?Ser216GluAla204His?+?Thr212Gly?+?Ala219Gln?+?Leu221ThrGly206Gln?+?Thr212Pro?+?Tyr213Met?+?Thr224ProTrp208Thr?+?Ile209Gln?+?Tyr213Ser?+?Ser222AspAla204Asn?+?Ile209Asn?+?Tyr213Pro?+?Leu221ProPro205Gly?+?Tyr210His?+?Tyr218Ile?+?Leu221AsnAla204Pro?+?Tyr210Cys?+?Pro214Gln?+?Thr215ProPro205Ser?+?Tyr213Ser?+?Ser216Asp?+?Thr217GlyPro205Asn?+?Trp208Ser?+?Ala219Glu?+?Ser220AspTyr210Ala?+?Tyr218Met?+?Ala219Glu?+?Ser220AspAla204Gly?+?Pro205Gln?+?Pro214Asp?+?Thr215AspTyr210Ser?+?Thr215Asn?+?Ser222Glu?+?Gly223GluGly206Pro?+?Tyr213Val?+?Ser222Glu?+?Gly223AspPro214Ser?+?Leu221Glu?+?Ser222Asp?+?Gly223GlnPro205Gln?+?Ser216Asp?+?Thr217Glu?+?Ala219ThrTrp208Leu?+?Thr212Gln?+?Ser220Glu?+?Leu221GluGly206Gln?+?Ser220Asp?+?Leu221Asp?+?Gly223AsnThr217Asp?+?Tyr218Asp?+?Gly223Ser?+?Thr224GlyPro205Gln?+?Ile209Ala?+?Thr217Glu?+?Tyr218GluPro214Gln?+?Thr215Asp?+?Ser216Glu?+?Thr224ProAla204His?+?Ser207Glu?+?Tyr213Cys?+?Ser222AspPro205Gly?+?Ser207Glu?+?Thr212Gln?+?Ser222AspSer207Glu?+?Tyr210Ser?+?Tyr218Leu?+?Ser222GluSer207Glu?+?Tyr218Cys?+?Ser222Glu?+?Thr224ProPro205Ser?+?Trp208Glu?+?Leu221Glu?+?Ser222GluTrp208Glu?+?Ile209Asn?+?Thr217Gly?+?Ser222GluSer216Glu?+?Thr217Asp?+?Tyr218Glu?+?Thr224GlyTrp208Asp?+?Tyr218Leu?+?Ala219Thr?+?Leu221GluAla204His?+?Thr212Gly?+?Thr215Glu?+?Thr217GluPro214Asp?+?Ser216Asp?+?Ala219His?+?Gly223AsnTyr210Pro?+?Pro214Asp?+?Ser216Glu?+?Tyr218IlePro205Gln?+?Tyr210Leu?+?Pro214Glu?+?Thr217AspAla204Ser?+?Ser207Glu?+?Pro214Ser?+?Gly223AspSer207Asp?+?Thr212Pro?+?Thr217Gly?+?Gly223AspSer207Glu?+?Pro214Asn?+?Ser220Glu?+?Ser222AspPro205Ser?+?Thr217Pro?+?Ala219Glu?+?Leu221GluTrp208Gln?+?Tyr210Glu?+?Thr212Asn?+?Leu221GluTrp208Gln?+?Thr215Pro?+?Ser220Glu?+?Ser222GluGly206Pro?+?Thr217Gly?+?Ser220Asp?+?Ser222GluGly206Gln?+?Tyr210Gly?+?Ser220Glu?+?Ser222AspSer207Glu?+?Thr212Asn?+?Tyr218Pro?+?Leu221AspAla204Asn?+?Ser207Glu?+?Trp208His?+?Leu221AspTyr213Ile?+?Tyr218Leu?+?Ser222Asp?+?Thr224GluGly206Gln?+?Tyr210Met?+?Ser222Asp?+?Thr224GluIle209Ser?+?Tyr210His?+?Ser222Glu?+?Thr224AspAla204Ser?+?Tyr218Asp?+?Ala219Pro?+?Ser220GluGly206Gln?+?Thr217Ser?+?Tyr218Glu?+?Ser220GluPro214Asp?+?Tyr218Asp?+?Gly223Ser?+?Thr224GlyGly206Gln?+?Tyr210Gly?+?Pro214Glu?+?Tyr218GluTrp208Asp?+?Thr217Gln?+?Ser220Asp?+?Gly223AspSer207Glu?+?Tyr210Ala?+?Thr215Asn?+?Ser220AspSer207Glu?+?Thr217Gly?+?Ser220Asp?+?Leu221GlnSer207Glu?+?Thr217Gly?+?Tyr218Asn?+?Ser220AspPro205Asn?+?Ser207Asp?+?Thr212Gly?+?Ser220AspSer207Glu?+?Thr212Asn?+?Ala219Gly?+?Ser220AspGly206Pro?+?Ser207Glu?+?Trp208Asp?+?Thr224AspSer207Asp?+?Trp208Thr?+?Tyr218Gln?+?Thr224GluAla204Thr?+?Ser207Asp?+?Leu221Ala?+?Thr224GluSer207Asp?+?Ala219Glu?+?Ser220Asp?+?Gly223SerSer207Glu?+?Tyr210Glu?+?Thr215Gln?+?Thr224AsnAla204Gln?+?Tyr210Glu?+?Thr212Asn?+?Ser222Asp
Table 26
Ring 6-five replacement varient Gly206Asn+Tyr210Gly+Thr212Gln+Tyr218Ile+
Thr224GlyAla204Asn?+?Pro205Gly?+?Trp208Glu?+?Thr215Asn?+
Gly223ProPro205Gln?+?Gly206Pro?+?Trp208Asn?+?Thr212Gln?+
Thr224SerAla204Ser?+?Pro205Ser?+?Tyr213Ser?+?Thr215Ser?+
Ala219GlyAla204Gly?+?Gly206Gln?+?Thr212Pro?+?Ser220Asp?+
Leu221SerPro214Ser?+?Thr215Gln?+?Tyr218Val?+?Ser222Asp?+
Thr224AsnAla204Pro?+?Ser207Asp?+?Tyr210Cys?+?Thr212Pro?+
Thr215ProGly206Asn?+?Pro214Gln?+?Ala219Gly?+?Gly223Asn?+
Thr224AspAla204Gln?+?Pro205Ser?+?Gly206Ser?+?Tyr210Gln?+
Ala219AspGly206Pro?+?Ser207Asp?+?Trp208Met?+?Thr215Pro?+
Leu221ProAla204Asn?+?Pro205Gln?+?Tyr210Cys?+?Thr212Asn?+
Leu221SerAla204Asn?+?Gly206Gln?+?Trp208Thr?+?Ile209Ser?+
Ser222AspPro205Gln?+?Tyr213Leu?+?Thr217Glu?+?Tyr218Met?+
Leu221GlnAla204Pro?+?Trp208Met?+?Ile209Val?+?Tyr210Leu?+
Ser216GluTrp208Ser?+?Ile209Ser?+?Tyr218His?+?Ala219His?+
Gly223ProTrp208Pro?+?Ile209Thr?+?Thr212Gly?+?Thr215Gly?+
Thr224GluIle209Val?+?Pro214Ser?+?Ser216Asp?+?Tyr218Met?+
Leu221MetGly206Gln?+?Ile209Gln?+?Ser220Asp?+?Leu221Gly?+
Thr224SerPro205Gln?+?Trp208Cys?+?Thr212Asn?+?Tyr213Cys?+
Pro214AspPro205Gln?+?Trp208Gln?+?Thr217Asp?+?Gly223Ser?+
Thr224GlySer207Glu?+?Thr212Ser?+?Thr217Gly?+?Tyr218Gln?+
Leu221HisTyr210His?+?Thr212Ser?+?Leu221Glu?+?Gly223Ser?+
Thr224ProTrp208Phe?+?Tyr213Met?+?Thr215Pro?+?Ser220Glu?+
Thr224GlyGly206Ser?+?Trp208Phe?+??Ile209Ser?+?Tyr213Cys?+
Ser216GluAla204Gln?+?Pro205Ser?+?Tyr210His?+?Tyr218Pro?+
Thr224GluPro205Gln?+?Gly206Gln?+?Leu221His?+?Ser222Asp?+
Gly223GlnAla204Gly?+?Ile209His?+?Tyr210Met?+?Ser216Glu?+
Thr217ProGly206Pro?+?Ile209Ala?+?Tyr210Gly?+?Leu221Asp?+
Gly223GlnGly206Asn?+?Tyr210Met?+?Thr215Glu?+?Gly223Asn?+
Thr224GlyGly206Gln?+?Ile209Pro?+?Ser216Asp?+?Leu221Cys?+
Gly223ProTrp208Thr?+?Tyr210Val?+?Thr212Ser?+?Pro214Asp?+
Gly223GlnThr212Gly?+?Pro214Gln?+?Thr215Ser?+?Leu221Gly?+
Thr224GluAla204Thr?+?Thr212Ser?+?Thr217Ser?+?Gly223Asp?+
Thr224ProPro205Ser?+?Ile209Pro?+?Tyr213Ile?+?Ala219Pro?+
Ser222GluTrp208Gly?+?Thr212Gln?+?Tyr218Gly?+?Ser222Glu?+
Gly223SerGly206Pro?+?Ile209Pro?+?Tyr213Ser?+?Thr217Gly?+
Tyr218ValPro205Gln?+?Tyr213Cys?+?Pro214Gln?+?Ser220Glu?+
Thr224GlyGly206Asn?+?Thr212Gly?+?Tyr213Asn?+?Tyr218Pro?+
Ser220GluAla204Pro?+?Pro205Ser?+?Thr212Gln?+?Thr217Asp?+
Thr224SerPro205Asn?+?Trp208Ile?+?Thr212Gln?+?Pro214Ser?+
Thr217GlyIle209Cys?+?Thr217Gly?+?Ser220Asp?+?Leu221Gln?+
Gly223GlnIle209Thr?+?Thr215Gly?+?Ser216Glu?+?Tyr218Leu?+
Ala219ProIle209Met?+?Pro214Gly?+?Thr217Gly?+?Tyr218Cys?+
Leu221MetPro205Gly?+?Pro214Asn?+?Tyr218Ile?+?Ala219Gly?+
Ser222AspTyr210Thr?+?Thr212Ser?+?Pro214Ser?+?Leu221Asn?+
Ser222AspGly206Asn?+?Tyr210Ile?+?Pro214Gln?+?Ala219Asn?+
Leu221ValPro205Asn?+?Thr215Ser?+?Ala219Ser?+?Leu221Ala?+
Thr224AspGly206Pro?+?Pro214Asn?+?Thr215Gln?+?Tyr218Ser?+
Leu221ThrAla204Pro?+?Gly206Gln?+?Ile209His?+?Thr212Gly?+
Gly223GluPro205Gln?+?Tyr213Gly?+?Tyr218Ala?+?Gly223Glu?+
Thr224ProPro205Ser?+?Pro214Gly?+?Thr217Pro?+?Ala219Thr?+
Leu221GluAla204Pro?+?Pro205Asn?+?Ser207Asp?+?Tyr210Ala?+
Pro214SerGly206Ser?+?Tyr213Thr?+?Ala219Gln?+?Ser220Glu?+
Gly223SerPro205Gly?+?Thr212Asn?+?Thr215Pro?+?Ser216Glu?+
Leu221AsnSer207Glu?+?Ile209Ala?+?Thr212Asn?+?Thr215Gln?+
Tyr218MetTyr213His?+?Thr215Gln?+?Thr217Asn?+?Ala219Glu?+
Leu221SerGly206Gln?+?Tyr213Asn?+?Thr215Ser?+?Tyr218Ala?+
Leu221AlaTrp208Met?+?Tyr210Met?+?Tyr218Gln?+?Ser220Glu?+
Thr224SerAla204Thr?+?Pro205Ser?+?Ile209Leu?+?Thr217Asn?+
Thr224ProPro205Gly?+?Ile209Leu?+?Thr215Asn?+?Ser216Glu?+
Gly223SerIle209Ser?+?Tyr213Leu?+?Thr217Asp?+?Tyr218Asn?+
Ala219HisAla204Ser?+?Pro205Ser?+?Ser207Glu?+?Leu221Val?+
G1y223ProAla204His?+?Thr212Gly?+?Ala219Gln?+?Leu221Thr?+
Gly223GluPro205Ser?+?Gly206Gln?+?Thr212Pro?+?Gly223Pro?+
Thr224ProAla204Asn?+?Trp208Thr?+?Tyr213Pro?+?Leu221Pro?+
Ser222AspPro205Gly?+?Ile209Met?+?Tyr218Met?+?Leu221Val?+
Gly223AsnThr212Gly?+?Tyr218Ile?+?Ala219Asn?+?Ser220Glu?+
Thr224ProAla204Gln?+?Pro205Gln?+?Gly206Gln?+?Ile209Met?+
Ser216AspAla204Thr?+?Thr212Gly?+?Ala219Asn?+?Gly223Asp?+
Thr224AsnAla204Pro?+?Trp208His?+?Tyr213Leu?+?Thr217Ser?+
Ser222GluPro205Ser?+?Ser207Asp?+?Ile209Asn?+?Tyr213Met?+
Thr217GlnGly206Pro?+?Trp208Ser?+?Thr212Gly?+?Tyr213Cys?+
Gly223GluAla204Asn?+?Gly206Pro?+?Trp208Val?+?Pro214Asn?+
Tyr218GluIle209Gly?+?Tyr210Ala?+?Tyr218Pro?+?Gly223Ser?+
Thr224SerPro205Gln?+?Tyr213His?+?Tyr218Met?+?Ser220Glu?+
Leu221GlyAla204Asn?+?Tyr210Cys?+?Thr212Gln?+?Tyr218Leu?+
Ser222AspGly206Ser?+?Ile209Leu?+?Thr212Gly?+?Pro214Gln?+
Thr215GluSer207Asp?+?Pro214Ser?+?Thr215Asn?+?Thr217Asn?+
Leu221SerPro205Gly?+?Trp208Thr?+?Thr217Gly?+?Ser220Glu?+
Gly223SerGly206Ser?+?Trp208Glu?+?Tyr210Gln?+?Thr217Gln?+
Leu221ProGly206Gln?+?Ser207Glu?+?Thr212Asn?+?Pro214Ser?+
Leu221AlaAla204Ser?+?Trp208Leu?+?Ile209Asn?+?Thr215Asp?+
Thr224AsnGly206Ser?+?Ile209Pro?+?Thr217Ser?+?Ser220Glu?+
Gly223GlnPro205Gln?+?Trp208Pro?+?Thr212Pro?+?Pro214Glu?+
Ala219SerGly206Pro?+?Ser207Glu?+?Tyr210Met?+?Thr212Gly?+
Tyr213LeuAla204His?+?Tyr210Pro?+?Tyr213Ala?+?Thr217Glu?+
Thr224SerTrp208Cys?+?Ile209Met?+?Tyr210Ala?+?Tyr213Met?+
Ala219AsnTrp208Thr?+?Tyr210Ala?+?Tyr218Met?+?Ala219Glu?+
Ser220AspTrp208Asn?+?Ile209Pro?+?Ala219Asp?+?Ser220Asp?+
Gly223SerPro205Ser?+?Tyr213Thr?+?Pro214Asp?+?Thr215Asp?+
Tyr218ValIle209Ser?+?Tyr213Pro?+?Leu221Met?+?Ser222Asp?+
Gly223AspAla204Thr?+?Thr217Gln?+?Tyr218Ile?+?Ser222Glu?+
Gly223AspPro205Ser?+?Tyr210Ala?+?Thr215Asn?+?Ser222Glu?+
Gly223GluTyr210Pro?+?Thr212Pro?+?Leu221Asn?+?Ser222Asp?+
Gly223AspTrp208Pro?+?Ile209Pro?+?Tyr213Ile?+?Ser222Asp?+
Gly223AspGly206Gln?+?Tyr213Gly?+?Thr217Gly?+?Ser222Glu?+
Gly223GluTrp208Ser?+?Ile209Pro?+?Thr212Pro?+?Ser216Glu?+
Thr217AspGly206Asn?+?Tyr218Met?+?Ala219His?+?Ser220Glu?+
Leu221AspIle209Ala?+?Thr215Glu?+?Ser216Glu?+?Gly223Gln?+
Thr224AsnIle209Gly?+?Pro214Ser?+?Thr215Glu?+?Ser216Asp?+
Tyr218IleAla204Ser?+?Trp208Val?+?Ile209Ser?+?Thr215Glu?+
Ser216AspThr212Pro?+?Thr215Asp?+?Ser216Glu?+?Thr217Glu?+
Thr224SerAla204His?+?Ser207Glu?+?Trp208His?+?Tyr210His?+
Ser222AspSer207Glu?+?Tyr213Asn?+?Leu221Thr?+?Ser222Asp?+
Thr224GlyGly206Ser?+?Ser207Glu?+?Trp208Pro?+?Ala219Thr?+
Ser222AspPro205Gly?+?Ser207Glu?+?Thr212Gln?+?Tyr213Gln?+
Ser222AspPro205Ser?+?Ser207Glu?+?Tyr213His?+?Thr217Pro?+
Ser222GluGly206Pro?+?Ser207Asp?+?Tyr213Ile?+?Tyr218Asn?+
Ser222GluGly206Pro?+?Trp208Glu?+?Tyr210Cys?+?Pro214Gln?+
Ser220AspTyr210Glu?+?Tyr213Gly?+?Tyr218Leu?+?Ala219Asp?+
Thr224SerGly206Pro?+?Ser207Asp?+?Leu221Asp?+?Ser222Glu?+
Thr224GlnTyr213Ser?+?Pro214Ser?+?Thr215Glu?+?Thr217Asp?+
Tyr218AlaAla204Asn?+?Tyr210Gln?+?Thr212Asn?+?Pro214Glu?+
Ser216AspPro205Gln?+?Gly206Pro?+?Pro214Glu?+?Ser216Asp?+
Thr224SerSer207Asp?+?Thr212Pro?+?Thr215Gly?+?Thr217Gly?+
Gly223AspSer207Glu?+?Tyr210Val?+?Pro214Asn?+?Leu221Thr?+
Gly223GluSer207Asp?+?Ile209Thr?+?Tyr210Met?+?Thr212Pro?+
Gly223AspSer207Glu?+?Tyr210Ser?+?Tyr218Leu?+?Ser220Asp?+
Ser222GluSer207Asp?+?Thr217Gln?+?Ser220Asp?+?Ser222Asp?+
Thr224AsnTrp208Thr?+?Thr217Glu?+?Tyr218Ser?+?Ala219Glu?+
Leu221CysPro205Gly?+?Thr212Ser?+?Ala219Gln?+?Ser220Glu?+
Ser222GluGly206Pro?+?Trp208His?+?Tyr210Gly?+?Ser220Glu?+
Ser222AspAla204Gln?+?Gly206Ser?+?Trp208Gln?+?Ser220Glu?+
Ser222GluAla204Ser?+?Tyr213Thr?+?Ser220Asp?+?Leu221Met?+
Ser222AspThr212Gly?+?Thr215Asp?+?Ser216Asp?+?Thr217Gly?+
Tyr218AspAla204Asn?+?Tyr210Glu?+?Tyr213Ala?+?Ser220Glu?+
Ser222GluAla204His?+?Gly206Pro?+?Ser216Glu?+?Tyr218Asp?+
Leu221SerGly206Pro?+?Ile209Ser?+?Tyr210His?+?Ser222Glu?+
Thr224AspTrp208Met?+?Tyr218Leu?+?Ala219Pro?+?Ser222Glu?+
Thr224GluTrp208Val?+?Tyr210Leu?+?Thr212Asn?+?Tyr218Asp?+
Ser220GluAla204Ser?+?Tyr213Gln?+?Tyr218Asp?+?Ala219Pro?+
Ser220GluThr212Asn?+?Tyr213Gln?+?Thr217Ser?+?Tyr218Glu?+
Ser220GluPro214Ser?+?Leu221Glu?+?Ser222Asp?+?Gly223Ser?+
Thr224AspPro205Gly?+?Tyr210Cys?+?Ala219Asp?+?Ser220Glu?+
Ser222AspGly206Gln?+?Tyr210Gly?+?Pro214Glu?+?Thr217Pro?+
Tyr218GluTrp208Asp?+?Pro214Ser?+?Thr217Gln?+?Ser220Asp?+
Gly223AspSer207Glu?+?Tyr210Ala?+?Thr215Asn?+?Ser220Asp?+
Leu221AlaSer207Asp?+?Trp208Cys?+?Ile209Ala?+?Thr215Asn?+
Ser220GluSer207Asp?+?Tyr210Met?+?Tyr218Asn?+?Ser220Glu?+
Leu221CysSer207Glu?+?Tyr210Pro?+?Thr215Gln?+?Tyr218Cys?+
Ser220GluSer207Glu?+?Thr212Ser?+?Pro214Gln?+?Ser220Asp?+
Leu221ProPro205Asn?+?Ser207Asp?+?Thr215Pro?+?Ser220Asp?+
Leu221ThrTrp208Glu?+?Ile209Asn?+?Thr217Gly?+?Ala219Asp?+
Ser222GluPro205Asn?+?Ser207Glu?+?Tyr213Leu?+?Ser220Asp?+
Gly223GluAla204Ser?+?Pro205Gly?+?Ser207Asp?+?Thr212Ser?+
Thr224AspAla204Pro?+?Gly206Gln?+?Ser207Glu?+?Tyr218Asn?+
Thr224GluGly206Ser?+?Ser207Glu?+?Tyr210Met?+?Tyr213Cys?+
Thr224AspPro205Asn?+?Ser207Glu?+?Ile209Val?+?Tyr213Pro?+
Thr224GluSer207Asp?+?Ile209Val?+?Tyr213Ala?+?Gly223Gln?+
Thr224GluPro205Asn?+?Ser207Glu?+?Ala219Glu?+?Ser220Glu?+
Gly223GlnGly206Asn?+?Ser207Glu?+?Trp208Asp?+?Ala219Asp?+
Thr224ProAla204Gly?+?Gly206Ser?+?Ser207Asp?+?Tyr210Asp?+
Leu221GlyAla204Pro?+?Ser207Glu?+?Ile209Thr?+?Tyr210Glu?+
Tyr218LeuIle209Thr?+?Tyr213Gly?+?Ala219Asp?+?Ser222Glu?+
Gly223AspPro205Gln?+?Tyr213Gln?+?Tyr218Glu?+?Leu221Glu?+
Ser222AspGly206Gln?+?Ser207Glu?+?Thr212Asn?+?Ser220Glu?+
Thr224GluSer207Glu?+?Thr217Gly?+?Tyr218Asn?+?Ser220Asp?+
Thr224GluAla204Thr?+?Tyr210Cys?+?Ser220Glu?+?Leu221Ser?+
Gly223GluIle209Pro?+?Ser216Glu?+?Ala219Glu?+?Ser220Asp?+
Gly223AsnGly206Gln?+?Tyr210Met?+?Thr212Pro?+?Ala219Glu?+
Ser222AspPro205Asn?+?Tyr210Glu?+?Thr217Asp?+?Tyr218Ala?+
Thr224ProAla204Gly?+?Trp208Gln?+?Thr212Gln?+?Ser216Asp?+
Ala219GluAla204Asn?+?Trp208Ala?+?Ser216Asp?+?Ala219Glu?+
Thr224GlyAla204Asn?+?Tyr210Asp?+?Thr215Glu?+?Thr217Glu?+
Ala219GlyTrp208Leu?+?Ile209Gly?+?Thr215Asp?+?Thr217Glu?+
Ser220AspThr212Pro?+?Tyr213Leu?+?Ser216Glu?+?Tyr218Glu?+
Leu221GluThr217Asp?+?Ala219Glu?+?Leu221Asn?+?Ser222Glu?+
Thr224SerPro205Ser?+?Trp208Glu?+?Tyr218Glu?+?Leu221Gly?+
Ser222GluSer207Glu?+?Thr215Pro?+?Thr217Asp?+?Ser220Glu?+
Gly223ProThr217Asp?+?Ala219Asn?+?Leu221Glu?+?Ser222Glu?+
Gly223AsnTrp208Tyr?+?Ile209Asn?+?Thr217Glu?+?Leu221Glu?+
Ser222AspAla204Gly?+?Tyr210Glu?+?Pro214Glu?+?Ser216Glu?+
Thr217AsnPro214Asp?+?Thr215Gln?+?Ser216Glu?+?Ser220Glu?+
Leu221MetAla204Gln?+?Tyr210Glu?+?Thr212Asn?+?Thr217Glu?+
Ser222AspTrp208Leu?+?Ile209Val?+?Thr215Asp?+?Thr217Glu?+
Leu221GluGly206Pro?+?Ile209Val?+?Tyr213Pro?+?Thr215Asp?+
Ala219GluPro205Asn?+?Ser207Glu?+?Tyr218Asp?+?Ser222Asp?+
Thr224GlyGly206Ser?+?Tyr210Asp?+?Pro214Asp?+?Thr215Pro?+
Leu221AspTyr210Ser?+?Pro214Asp?+?Tyr218Cys?+?Ser220Glu?+
Ser222GluSer207Asp?+?Ile209Ser?+?Thr212Ser?+?Pro214Asp?+
Thr215Asp
Table 27
Ring 6 - six substituted variants Gly206Asn + Tyr210Gly + Thr212Gln + Tyr213Gly + Tyr218Ile + Thr224Gly Pro205Asn + Gly206Ser + Tyr213Gly + Ser216Asp + Thr217Ser + Thr224Asn Ala204Ser + Pro205Ser + Tyr213Ser + Tyr218His + Ala219Gln + Leu221Asn Ser207Glu + Thr212Gln + Thr215Pro + Tyr218Gln + Leu221Met + Gly223Gln Pro205Ser + Ser207Asp + Tyr210Val + Tyr213Leu + Leu221Gln + Thr224Gly Ala204Ser + Trp208Cys + Ile209His + Thr215Glu + Thr217Pro + Gly223Ser Ala204Gly + Ile209Asn + Tyr210Ile + Ser216Asp + Ala219Asn + Leu221Met Ala204Gly + Pro205Gln + Pro214Glu + Thr215Ser + Tyr218Asn + Thr224Ser Gly206Asn + Trp208Cys + Thr212Gly + Tyr213Gly + Ser216Asp + Leu221His Trp208Pro + Ile209Gly + Thr215Ser + Ala219Thr + Leu221Thr + Thr224Asp Pro205Gly + Gly206Gln + Ile209Gly + Thr212Asn + Pro214Asn + Ser220Glu Pro205Gly + Trp208Leu + Thr217Gln + Leu221Gln + Gly223Gln + Thr224Glu Ala204Gly + Gly206Asn + Tyr210Cys + Tyr213Thr + Gly223Asp + Thr224Asn Gly206Asn + Trp208His + Ile209Gly + Thr217Gly + Leu221Val + Thr224Pro Ala204Thr + Thr212Gln + Tyr213Gln + Thr217Ser + Ser222Asp + Thr224Pro Trp208Gly + Thr212Gln + Tyr213Leu + Tyr218Gly + Ser222Glu + Gly223Ser Pro205Ser + Trp208Ser + Tyr213Asn + Tyr218Gln + Ser222Asp + Thr224Gln Ala204His + Pro205Gly + Ile209Asn + Tyr213Gln + Thr215Ser + Thr217Ser Ala204Thr + Gly206Asn + Trp208Leu + Thr215Ser + Ser216Asp + Ala219His Gly206Ser + Thr212Gln + Tyr213Val + Tyr218Cys + Ser220Glu + Thr224Gln Gly206Asn + Trp208Ile + Ile209Ser + Tyr218Gln + Gly223Glu + Thr224Gly Gly206Asn + Ser207Glu + Ile209Cys + Thr212Ser + Thr217Pro + Ala219His Ala204Asn + Tyr210Cys + Tyr213Asn + Tyr218Leu + Leu221His + Ser222Glu Gly206Pro + Tyr213Asn + Pro214Asn + Thr215Gln + Tyr218Ser + Leu221Thr Ala204Pro + Pro205Asn + Gly206Gln + Ile209His + Thr212Gly + Gly223Glu Pro205Gln + Tyr213Gly + Thr215Gly + Tyr218Ala + Gly223Glu + Thr224Pro Ala204His + Ser207Glu + Trp208Gly + Ile209His + Tyr213Cys + Thr215Ser Gly206Ser + Trp208His + Tyr213Thr + Ala219Gln + Ser220Glu + Gly223Ser Tyr213His + Thr215Gln + Thr217Asn + Tyr218Ala + Ala219Glu + Leu221Ser Ala204Asn + Pro205Ser + Gly206Asn + Ile209Leu + Thr215Asp + Thr224Pro Pro205Ser + Ile209Gly + Tyr213Leu + Thr217Asp + Tyr218Asn + Ala219His Ala204Asn + Pro205Gln + Ser207Asp + Tyr210Val + Thr212Gly + Leu221Thr Ala204Asn + Trp208Thr + Ile209Gln + Tyr213Pro + Leu221Pro + Ser222Asp Ala204Ser + Gly206Ser + Tyr213Gly + Pro214Gln + Tyr218Val + Ser222Asp Ala204Pro + Tyr210Cys + Tyr213Ser + Pro214Gln + Thr215Pro + Thr217Gly Thr212Ser + Pro214Asp + Thr217Gly + Ala219Thr + Leu221Pro + Thr224Gln Pro205Gln + Gly206Gln + Ser207Glu + Tyr210Gly + Thr212Pro + Tyr218Gly Pro205Gln + Gly206Pro + Trp208Asn + Ile209Met + Tyr213Ser + Ala219Asp Ala204Asn + Ser207Glu + Trp208Ala + Tyr213Asn + Leu221Thr + Thr224Gly Ala204Pro + Trp208His + Ile209Asn + Tyr213Leu + Thr217Ser + Ser222Glu Gly206Pro + Trp208Ser + Tyr210Val + Thr212Gly + Tyr213Cys + Ala219Asp Pro205Gly + Gly206Gln + Ile209Cys + Tyr210His + Thr215Gln + Ala219Thr Trp208Gly + Ile209Ser + Thr212Gln + Tyr218Met + Leu221Ser + Gly223Ser Pro205Asn + Ile209Asn + Thr212Asn + Thr217Glu + Gly223Pro + Thr224Ser Pro205Gly + Trp208Thr + Thr212Ser + Ser216Glu + Thr217Gly + Gly223Ser Gly206Ser + Trp208Glu + Tyr210Gln + Thr215Gly + Thr217Gln + Leu221Pro Gly206Ser + Ser207Glu + Trp208Leu + Thr212Asn + Leu221Ala + Thr224Asn Ala204Asn + Pro205Gln + Gly206Gln + Trp208Ile + Ser216Asp + Tyr218Cys Ala204Thr + Tyr210Cys + Tyr213Ser + Thr215Ser + Ser216Asp + Ala219His Trp208Leu + Ile209Asn + Thr212Gly + Thr215Ser + Tyr218Pro + Leu221Gly Pro205Gly + Gly206Gln + Tyr218Gly + Ala219Asn + Leu221Gln + Thr224Ser Pro205Gln + Trp208Val + Tyr210Pro + Thr215Gly + Ala219Ser + Thr224Glu Pro205Gly + Trp208Met + Ile209Ser + Thr212Asn + Tyr218Ala + Ala219Thr Thr212Gly + Tyr213Asn + Pro214Ser + Ser216Glu + Thr217Pro + Leu221Thr Ala204Gly + Trp208Pro + Ile209Pro + Tyr213Gln + Tyr218Ser + Ser220Glu Ala204Gly + Gly206Asn + Ile209Met + Thr212Pro + Ala219Glu + Leu221Met Pro205Asn + Gly206Pro + Trp208Leu + Tyr210Pro + Thr217Gln + Tyr218Glu Pro205Asn + Gly206Gln + Tyr213Val + Ser220Asp + Gly223Ser + Thr224Asn Ala204Thr + Pro205Gly + Gly206Gln + Pro214Gln + Leu221Val + Gly223Gln Pro205Ser + Ile209Gln + Thr212Pro + Ala219Gly + Ser220Glu + Gly223Gln Ala204Gly + Gly206Gln + Ile209Leu + Thr212Asn + Pro214Gln + Thr215Ser Gly206Asn + Trp208Ser + Thr212Ser + Pro214Asn + Ser220Glu + Gly223Ser Ala204His + Tyr213Leu + Pro214Asn + Thr217Pro + Ser220Glu + Gly223Gln Gly206Pro + Ile209Cys + Pro214Gln + Thr217Ser + Tyr218Cys + Ala219Gln Ala204Thr + Tyr210Ala + Thr215Gly + Thr217Gln + Ala219Pro + Ser220Asp Ser207Asp + Ile209Thr + Thr212Gly + Thr217Pro + Ala219Gly + Thr224Pro Ala204Gly + Ser207Glu + Thr212Asn + Pro214Ser + Tyr218Ser + Ala219Ser Pro205Gln + Gly206Gln + Thr212Ser + Tyr213Ala + Thr215Ser + Gly223Glu Pro205Ser + Tyr210Ala + Pro214Ser + Thr215Asn + Ser222Asp + Gly223Glu Ile209Pro + Tyr210Pro + Thr212Pro + Leu221Asn + Ser222Asp + Gly223Asp Pro205Ser + Thr212Ser + Tyr213Ile + Ala219Pro + Ser222Glu + Gly223Asp Ala204Asn + Ile209Cys + Tyr213Cys + Tyr218Ala + Leu221Asp + Ser222Glu Ile209Val + Thr212Asn + Tyr213Met + Thr217Asn + Gly223Asp + Thr224Asp Pro205Gly + Ile209Asn + Thr212Asn + Ser216Glu + Thr217Glu + Tyr218Gln Ala204His + Trp208Ser + Thr212Pro + Tyr213Pro + Ser216Glu + Thr217Asp Pro205Ser + Ile209Ala + Thr212Gly + Ser216Asp + Thr217Glu + Ala219Thr Pro205Ser + Trp208Met + Pro214Asn + Ala219Gln + Ser220Glu + Leu221Asp Ala204Pro + Gly206Ser + Tyr213Ile + Ser220Glu + Leu221Asp + Gly223Ser Gly206Pro + Tyr210Gly + Tyr213His + Thr217Glu + Tyr218Asp + Leu221Asn Thr212Pro + Tyr213Ser + Thr215Asp + Ser216Asp + Tyr218Pro + Gly223Gln Ser207Glu + Ile209Asn + Thr212Ser + Thr217Gly + Ser222Glu + Thr224Gln Pro205Gly + Ser207Glu + Tyr210Ser + Pro214Gln + Ser222Asp + Gly223Asn Gly206Pro + Ser207Asp + Trp208Ser + Pro214Ser + Leu221Asn + Ser222Asp Gly206Gln + Ser207Asp + Ile209Cys + Tyr210Met + Thr217Asn + Ser222Glu Gly206Pro + Ser207Glu + Ile209Pro + Tyr210Ile + Leu221Asn + Ser222Glu Pro205Ser + Ser207Glu + Trp208His + Thr215Pro + Leu221Asn + Ser222Glu Pro205Asn + Ser207Asp + Thr215Gln + Tyr218Ile + Leu221Gly + Ser222Glu Ala204Pro + Ser207Asp + Tyr210Cys + Thr212Pro + Thr215Pro + Ser222Glu Pro205Gly + Pro214Asp + Thr215Glu + Ser216Asp + Thr217Pro + Gly223Gln Ile209Thr + Thr217Gly + Ala219Glu + Ser220Asp + Leu221Glu + Gly223Ser Ala204Gln + Ser207Asp + Ile209Thr + Tyr218Asn + Ser222Glu + Gly223Asp Pro205Ser + Ser207Glu + Pro214Gly + Thr215Asn + Ser222Asp + Gly223Glu Pro205Asn + Gly206Pro + Trp208Asp + Thr212Gln + Ser222Asp + Gly223Ser Gly206Gln + Pro214Asp + Thr215Asp + Thr217Asp + Gly223Ser + Thr224Gly Ala204His + Ile209Thr + Ser216Asp + Thr217Asp + Tyr218Asp + Leu221Ser Thr212Asn + Pro214Gln + Tyr218Met + Ser222Glu + Gly223Asp + Thr224Glu Ala204Gln + Gly206Pro + Tyr210Glu + Pro214Gly + Ala219Asp + Leu221Gln Ala204Gly + Pro205Gln + Trp208Asp + Ile209Gln + Pro214Gly + Leu221Glu Ala204Asn + Gly206Gln + Ser207Glu + Trp208His + Leu221Asp + Ser222Asp Trp208Gly + Tyr213Ser + Pro214Ser + Thr215Glu + Thr217Asp + Tyr218Ala Ala204Asn + Pro205Ser + Tyr210Pro + Pro214Asp + Ser216Glu + Tyr218Ile Gly206Gln + Ile209Leu + Thr212Gly + Pro214Asp + Ser216Glu + Leu221His Pro205Gln + Trp208Glu + Tyr210Asp + Thr212Gln + Tyr213Asn + Thr215Ser Ser207Asp + Thr212Pro + Thr215Gly + Thr217Gln + Leu221Met + Gly223Asp Ala204Asn + Pro205Gln + Ser207Glu + Trp208Met + Ala219Pro + Gly223Asp Ala204Thr + Ser207Asp + Thr212Gly + Ala219Asn + Gly223Asp + Thr224Asn Ser207Asp + Pro214Asn + Thr215Gly + Tyr218Ala + Leu221Ser + Gly223Asp Ser207Glu + Thr212Asn + Tyr213Gln + Tyr218Pro + Ser220Glu + Leu221Asp Ala204Asn + Gly206Ser + Ser207Asp + Tyr210Thr + Ser220Asp + Leu221Asp Gly206Ser + Thr212Asn + Thr215Pro + Tyr218Val + Leu221Asp + Gly223Asp Trp208Met + Tyr210Thr + Thr212Asn + Ala219Gln + Leu221Asp + Gly223Asp Gly206Ser + Ser207Glu + Pro214Ser + Ala219Asn + Ser220Glu + Ser222Glu Ala204His + Ser207Glu + Ala219Ser + Ser220Glu + Leu221His + Ser222Asp Pro205Ser + Ser207Glu + Tyr213His + Thr217Pro + Ser220Glu + Ser222Glu Ser207Glu + Ile209Met + Tyr210Gly + Tyr213Leu + Ser220Glu + Ser222Asp Ser207Asp + Tyr213Pro + Pro214Gln + Ser220Glu + Ser222Glu + Gly223Pro Gly206Ser + Trp208Gln + Tyr210Glu + Thr212Asn + Thr215Gly + Leu221Glu Pro205Gly + Thr212Ser + Tyr218Leu + Ala219Gln + Ser220Glu + Ser222Glu Trp208Phe + Thr212Asn + Pro214Ser + Ser220Glu + Ser222Asp + Gly223Gln Ala204Gly + Gly206Pro + Tyr210Ser + Tyr218Cys + Ser220Glu + Ser222Asp Pro205Ser + Trp208Leu + Tyr213Ala + Thr217Ser + Ser220Asp + Ser222Asp Pro205Gly + Trp208His + Tyr210His + Ser220Glu + Leu221Gln + Ser222Asp Pro205Gly + Thr212Gln + Ala219Thr + Ser220Glu + Ser222Asp + Gly223Pro Ala204Ser + Gly206Pro + Tyr210Gly + Ser220Glu + Leu221Ser + Ser222Asp Ile209Ser + Tyr210Ser + Thr212Asn + Tyr213Cys + Ser220Asp + Ser222Glu Ala204Asn + Pro205Gly + Ser207Asp + Ile209Ser + Tyr213Val + Leu221Glu Ala204Asn + Gly206Pro + Thr215Glu + Ser216Glu + Thr217Asn + Tyr218Glu Gly206Pro + Ile209Ser + Tyr210His + Thr217Gly + Ser222Glu + Thr224Asp Gly206Gln + Thr217Gly + Ser220Asp + Ser222Glu + Gly223Glu + Thr224Ser Gly206Gln + Trp208Gin + Ile209Gln + Ser216Asp + Tyr218Asp + Ala219Glu Gly206Asn + Thr212Pro + Pro214Ser + Thr217Glu + Tyr218Glu + Ser220Glu Gly206Gln + Trp208Ser + Tyr210Asp + Pro214Gln + Thr217Glu + Ala219Asp Gly206Ser + Ser207Glu + Trp208Pro + Tyr210Asp + Ala219Thr + Ser222Asp Trp208Gly + Tyr210His + Thr212Ser + Pro214Glu + Tyr218Asp + Leu221Ile Ala204Gln + Gly206Gln + Tyr210Gly + Pro214Glu + Thr217Pro + Tyr218Glu Ala204His + Pro214Glu + Thr215Gln + Thr217Gln + Tyr218Glu + Leu221Pro Ser207Asp + Ile209Cys + Thr215Pro + Tyr218His + Ala219Thr + Ser220Glu Pro205Asn + Ser207Glu + Trp208Tyr + Ile209Asn + Thr217Gln + Ser220Glu Ser207Asp + Pro214Ser + Thr215Asn + Thr217Asn + Ser220Glu + Leu221Ser Pro205Gly + Ser207Asp + Tyr210Ser + Ser220Asp + Gly223Pro + Thr224Ser Gly206Gln + Ser207Glu + Ile209Gln + Ser220Asp + Leu221Ala + Thr224Ser Ala204Ser + Pro205Gly + Ser207Asp + Thr212Ser + Thr215Gln + Ser220Glu Pro205Ser + Ser207Asp + Thr217Gln + Ala219His + Ser220Glu + Gly223Glu Ser207Glu + Thr215Gln + Tyr218Val + Ser220Asp + Gly223Glu + Thr224Asn Pro205Gly + Ile209Pro + Tyr210Asp + Ala219Asp + Ser222Asp + Gly223Ser Gly206Asn + Tyr210Gln + Pro214Asn + Thr215Glu + Tyr218Glu + Leu221Ala Ile209Asn + Tyr210Asp + Thr212Gln + Ser222Glu + Gly223Pro + Thr224Asn Ala204Gly + Gly206Gln + Ser220Asp + Leu221Asp + Gly223Asn + Thr224Glu Gly206Pro + Thr212Pro + Thr217Pro + Tyr218Asn + Leu221Glu + Thr224Glu Ile209His + Tyr210Leu + Tyr213Leu + Pro214Asp + Thr217Asp + Ser220Glu Ile209Asn + Tyr210Ile + Thr212Asn + Thr215Gly + Ser220Asp + Gly223Glu Gly206Gln + Tyr210Ala + Thr215Asn + Ser216Glu + Thr217Asp + Ser220Asp Trp208Thr + Tyr213Pro + Tyr218His + Ala219Glu + Leu221Cys + Ser222Asp Ala204Gly + Trp208Gln + Thr212Gln + Ser216Asp + Ala219Glu + Gly223Ser Gly206Ser + Pro214Gly + Ser216Asp + Tyr218Pro + Ala219Glu + Leu221Pro Pro205Asn + Tyr210Asn + Thr217Glu + Ala219Gln + Ser220Glu + Gly223Gln Ala204Thr + Tyr213Ala + Pro214Gln + Thr215Gln + Thr217Asp + Ser220Glu Trp208Gln + Tyr210His + Thr217Asp + Tyr218Met + Ser220Asp + Thr224Ser Ala204Asn + Gly206Pro + Tyr210Asp + Pro214Glu + Ser220Glu + Thr224Asn Tyr213Ile + Ser216Glu + Tyr218His + Ala219Glu + Leu221Asp + Thr224Ser Pro205Ser + Trp208Glu + Tyr218Glu + Leu221Gly + Ser222Glu + Thr224Gly Ser207Asp + Tyr213Met + Pro214Gly + Thr217Gln + Tyr218Asp + Ala219Glu Trp208Phe + Ala219Asp + Leu221Ala + Ser222Asp + Gly223Asn + Thr224Glu Gly206Pro + Ile209His + Pro214Glu + Ser220Asp + Leu221Glu + Thr224Pro Trp208Tyr + Ile209Asn + Thr212Asn + Thr217Glu + Leu221Glu + Ser222Asp Pro205Gly + Ser216Glu + Thr217Glu + Ala219Gln + Leu221Glu + Gly223Gln Pro214Asn + Thr217Pro + Ala219Asp + Ser220Asp + Leu221Gln + Thr224Asp Ala204His + Gly206Asn + Ile209His + Pro214Glu + Ser216Asp + Ser220Glu Ser207Asp + Tyr210Glu + Thr217Asp + Tyr218Ala + Leu221Ile + Thr224Pro Thr212Gly + Tyr213Ala + Pro214Glu + Leu221Glu + Ser222Asp + Thr224Ser Pro205Gln + Gly206Asn + Thr212Gln + Tyr218Glu + Ser222Asp + Gly223Asp Pro205Gln + Thr212Gly + Tyr213Ala + Thr217Glu + Tyr218Glu + Ser222Glu Ile209Gln + Tyr213Ala + Pro214Glu + Ala219Asp + Ser222Asp + Thr224Pro Ala204Gly + Tyr210Pro + Pro214Glu + Ala219Glu + Leu221Asn + Ser222Asp Gly206Pro + Thr212Asn + Tyr213Thr + Pro214Asp + Ser220Asp + Ser222Glu Ala204Thr + Tyr213Ser + Pro214Asp + Ala219Asn + Ser220Asp + Ser222Glu Ala204His + Gly206Asn + Tyr210Pro + Pro214Glu + Ser220Glu + Ser222Glu Ser207Asp + Trp208Met + Pro214Glu + Thr215Asp + Thr217Ser + Gly223Pro Trp208Cys + Ile209Ser + Pro214Glu + Ser222Asp + Gly223Asp + Thr224Gly Pro205Asn + Thr212Asn + Tyr213Leu + Thr215Asp + Ser222Asp + Gly223Glu ...
Table 28
Ring 6 - seven substituted mutant Gly206Asn + Tyr210Gly + Thr212Gln + Thr215Gln + Tyr218Ile + Leu221Ile + Thr224Gly Ala204Ser + Pro205Ser + Ile209Met + Tyr213Ser + Tyr218His + Ala219Gln + Leu221Asn Ala204Gly + Trp208Gln + Thr212Gln + Ser216Asp + Tyr218Gln + Leu221Met + Gly223Ser Gly206Gln + Ile209Leu + Tyr210Ala + Thr212Gly + Tyr213Gly + Ser216Asp + Gly223Gln Ala204Gln + Pro205Asn + Gly206Asn + Trp208Ile + Tyr210Gln + Thr215Gln + Ala219Asp Ala204Asn + Pro205Gln + Ile209Ala + Tyr213Leu + Thr217Glu + Tyr218Met + Leu221Gln Pro205Gly + Ile209Gln + Thr212Ser + Ala219Gln + Ser220Glu + Leu221Cys + Thr224Ser Gly206Asn + Trp208Cys + Thr212Gly + Tyr213Gly + Ser216Asp + Thr217Gly + Leu221His Ala204Gln + Pro205Ser + Tyr210His + Thr212Pro + Tyr218Pro + Ala219Ser + Thr224Glu Ala204Gly + Gly206Asn + Tyr210Cys + Tyr213Thr + Thr215Gly + Gly223Asp + Thr224Asn Ala204Gln + Pro205Ser + Gly206Gln + Thr212Asn + Tyr218Cys + Ala219His + Gly223Glu Ala204Ser + Gly206Asn + Ile209Gly + Pro214Gly + Thr217Gly + Leu221Val + Thr224Pro Pro205Gly + Ile209Gln + Pro214Asn + Tyr218Ile + Ala219Gly + Leu221Met + Ser222Asp Ala204Asn + Trp208Ala + Ile209Gln + Pro214Gly + Thr217Glu + Tyr218Leu + Gly223Asn Gly206Asn + Tyr210Glu + Tyr213Gly + Thr217Gln + Tyr218Leu + Ala219Thr + Thr224Ser Gly206Pro + Ile209His + Tyr213Asn + Pro214Asn + Thr215Gln + Tyr218Ser + Leu221Thr Pro205Gly + Gly206Ser + Trp208His + Tyr213Thr + Ala219Gln + Ser220Glu + Gly223Ser Pro205Gln + Gly206Ser + Trp208Val + Tyr210Leu + Thr212Asn + Tyr218Met + Ser220Glu Ala204His + Gly206Asn + Tyr210Ser + Pro214Ser + Thr217Gln + Tyr218His + Ser222Asp Gly206Gln + Tyr213Asn + Thr215Gly + Ser216Glu + Thr217Gly + Tyr218His + Gly223Asn Gly206Gln + Ser207Glu + Tyr210Gly + Thr212Pro + Tyr213Met + Gly223Pro + Thr224Pro Ala204Asn + Trp208Thr + Ile209Gln + Tyr213Pro + Thr217Ser + Leu221Pro + Ser222Asp Ala204Ser + Gly206Gln + Trp208Asn + Thr212Ser + Ala219Gln + Ser220Glu + Leu221Asn Pro205Gly + Gly206Gln + Ile209Asn + Tyr213Val + Thr215Gln + Thr217Ser + Ala219Thr Ala204Ser + Pro205Gln + Ile209Asn + Thr212Asn + Thr217Glu + Gly223Pro + Thr224Ser Thr212Gly + Tyr213Ile + Pro214Gly + Tyr218Gly + Ala219Pro + Leu221Asn + Thr224Glu Ala204Asn + Tyr210Asp + Thr212Pro + Tyr213Asn + Thr217Asn + Tyr218Cys + Leu221His Ala204Gln + Ile209Cys + Tyr210Gln + Thr212Gly + Tyr213Gln + Gly223Pro + Thr224Asp Pro205Gln + Gly206Gln + Trp208Thr + Tyr210Leu + Thr215Gly + Thr217Gly + Tyr218Leu Tyr210Ala + Tyr213Val + Pro214Gln + Ala219Ser + Leu221Cys + Ser222Glu + Thr224Asn Ala204Asn + Gly206Pro + Ser207Asp + Trp208His + Ile209His + Pro214Gln + Leu221Gln Ala204Asn + Gly206Asn + Trp208Ile + Ile209Asn + Ser216Glu + Ala219Pro + Gly223Asn Ala204Ser + Gly206Ser + Ile209Ala + Thr212Ser + Pro214Gln + Tyr218Asp + Leu221His Gly206Asn + Ile209Pro + Tyr213Cys + Thr215Gln + Ser216Glu + Thr217Pro + Ala219His Ala204Gln + Trp208His + Tyr210Gly + Thr212Gln + Tyr218Met + Ala219Asn + Ser220Glu Ala204Pro + Ser207Asp + Tyr213Val + Pro214Gly + Thr215Gly + Tyr218Ala + Leu221Gln Pro205Asn + Gly206Pro + Trp208Leu + Tyr210Pro + Pro214Asn + Thr217Gln + Tyr218Glu Pro205Asn + Gly206Gln + Tyr213Val + Ala219Gln + Ser220Asp + Gly223Ser + Thr224Asn Gly206Pro + Ile209Cys + Tyr210Ser + Thr212Asn + Tyr213Cys + Pro214Gln + Tyr218Cys Ala204His + Trp208Asn + Thr212Pro + Pro214Gln + Thr215Asn + Thr217Gly + Thr224Asp Pro205Ser + Gly206Ser + Tyr210Ser + Thr215Pro + Ala219Asn + Leu221Met + Ser222Asp Ala204Ser + Gly206Gln + Trp208Pro + Thr212Asn + Thr215Glu + Tyr218Ile + Gly223Asn Ala204Ser + Pro205Asn + Trp208Tyr + Thr215Gly + Tyr218Pro + Ser220Glu + Thr224Gly Ala204Asn + Tyr210His + Pro214Asn + Tyr218Pro + Ala219Gln + Ser220Glu + Leu221Ile Ala204Gly + Gly206Asn + Ser207Asp + Thr212Asn + Tyr213Leu + Thr215Pro + Gly223Pro Ala204Asn + Tyr210Met + Thr212Gln + Pro214Gly + Ala219Gly + Ser222Asp + Gly223Gln Tyr210Pro + Thr212Gly + Tyr213Leu + Thr215Gly + Thr217Gly + Ala219Glu + Ser220Asp Gly206Ser + Trp208Asn + Ile209Pro + Ala219Asp + Ser220Asp + Gly223Ser + Thr224Gly Pro205Ser + Tyr210Cys + Tyr213Thr + Pro214Asp + Thr215Asp + Tyr218Val + Leu221Ser Trp208His + Ile209Val + Thr212Pro + Tyr213Leu + Thr217Ser + Ser222Glu + Gly223Glu Pro205Gly + Gly206Gln + Tyr210Asn + Tyr213Gly + Thr217Gly + Ser222Glu + Gly223Glu Ala204Thr + Thr212Gln + Tyr213Gln + Thr217Ser + Ser222Asp + Gly223Asp + Thr224Pro Pro205Gly + Ile209Cys + Tyr213Val + Pro214Gln + Thr215Pro + Ser222Glu + Gly223Asp Trp208Ser + Ile209Ser + Ser216Glu + Thr217Glu + Tyr218Gly + Ala219His + Gly223Pro Gly206Pro + Tyr210Gln + Thr212Pro + Tyr213Leu + Ser216Glu + Thr217Asp + Leu221Pro Trp208Met + Ile209Gln + Tyr210Met + Tyr218Gln + Ser220Glu + Leu221Glu + Thr224Ser Ile209Gln + Thr212Ser + Tyr213Val + Thr215Asp + Ser216Glu + Tyr218Met + Ala219Pro Tyr213Pro + Pro214Gln + Thr215Asp + Ser216Glu + Thr217Asp + Tyr218Met + Leu221Ala Ala204His + Pro205Gly + Ser207Glu + Trp208His + Tyr210His + Tyr213Cys + Ser222Asp Gly206Pro + Ser207Asp + Trp208Ser + Pro214Ser + Leu221Asn + Ser222Asp + Gly223Pro Ser207Glu + Trp208Tyr + Ile209Gly + Tyr213Thr + Pro214Ser + Tyr218Met + Ser222Glu Pro205Ser + Ser207Asp + Trp208Ser + Thr212Gly + Tyr213Asn + Tyr218Gln + Ser222Asp Ala204Thr + Gly206Asn + Trp208Thr + Thr212Gln + Pro214Glu + Thr215Asp + Ser216Asp Ala204Thr + Gly206Asn + Ser207Glu + Tyr210Ile + Leu221Thr + Ser222Glu + Gly223Glu Ala204His + Ser207Glu + Thr215Gln + Thr217Gln + Tyr218Asn + Ser222Glu + Gly223Glu Ala204Gln + Trp208Asp + Tyr210Thr + Thr212Ser + Thr217Asn + Ser222Asp + Gly223Asn Ile209Thr + Ser216Asp + Thr217Asp + Tyr218Asp + Leu221Ser + Gly223Ser + Thr224Gly Ala204Asn + Gly206Gln + Ser207Glu + Trp208His + Thr212Ser + Leu221Asp + Ser222Asp Gly206Ser + Ser207Asp + Tyr210Val + Thr212Gln + Tyr218Ile + Leu221Asp + Ser222Asp Ala204Ser + Gly206Pro + Pro214Gly + Thr215Asp + Thr217Asp + Tyr218Pro + Gly223Pro Gly206Gln + Ile209His + Pro214Asp + Thr215Pro + Ser216Asp + Leu221Gly + Thr224Ser Gly206Asn + Ser207Glu + Trp208Asp + Ile209Gly + Tyr213Gly + Ser220Glu + Ser222Glu Pro205Ser + Ser207Asp + Ile209Asn + Tyr213Met + Thr217Gln + Ala219His + Gly223Glu Pro205Gly + Gly206Gln + Ser207Glu + Ala219Pro + Ser220Asp + Leu221Glu + Thr224Ser Trp208Met + Tyr210Thr + Thr212Asn + Ala219Gln + Leu221Asp + Gly223Asp + Thr224Gln Pro205Ser + Ser207Glu + Tyr213His + Thr217Pro + Ala219Ser + Ser220Glu + Ser222Glu Ser207Asp + Tyr210Met + Pro214Ser + Tyr218Asn + Ser220Glu + Leu221Cys + Ser222Glu Ala204Pro + Ser207Glu + Pro214Gln + Ser220Asp + Leu221His + Ser222Asp + Thr224Ser Ser207Glu + Ile209Met + Tyr210Gly + Tyr213Leu + Thr215Gln + Ser220Glu + Ser222Asp Gly206Pro + Ser207Asp + Ile209Ser + Tyr210His + Thr217Gly + Ser222Glu + Thr224Asp Pro205Asn + Tyr210Cys + Tyr213Gly + Thr217Asn + Tyr218Met + Ser220Glu + Ser222Asp Ile209Gly + Thr212Pro + Thr215Asn + Thr217Gly + Ala219His + Ser220Glu + Ser222Glu Ala204Gln + Gly206Gln + Thr212Pro + Ser220Glu + Leu221Val + Ser222Asp + Thr224Gln Ala204Gln + Pro205Ser + Gly206Ser + Trp208Gln + Thr215Pro + Ser220Glu + Ser222Glu Ser207Glu + Trp208Leu + Tyr210Ile + Thr212Gly + Tyr218Cys + Leu221Asp + Gly223Asn Pro205Gly + Gly206Pro + Ser207Asp + Ile209Met + Leu221Asp + Ser222Glu + Thr224Asp Pro205Gly + Thr215Asn + Thr217Pro + Tyr218Val + Leu221Thr + Ser222Glu + Thr224Asp Trp208Phe + Tyr213Met + Thr215Asn + Tyr218Asp + Ala219Pro + Ser220Glu + Thr224Gly Ala204Pro + Pro205Gly + Trp208Leu + Thr217Gln + Leu221Asp + Ser222Glu + Thr224Asp Ile209Ala + Thr212Gln + Thr217Gln + Tyr218Thr + Ser220Glu + Leu221Asp + Gly223Glu Ala204Asn + Ile209Cys + Tyr213Cys + Tyr218Ala + Ala219Glu + Leu221Asp + Ser222Glu Gly206Ser + Ser207Glu + Trp208His + Tyr210Asp + Tyr218Val + Ala219Thr + Ser222Asp Pro205Gly + Ser207Asp + Trp208Thr + Thr212Ser + Thr217Gly + Ser220Glu + Gly223Ser Ser207Glu + Trp208Asn + Tyr210Pro + Pro214Asn + Tyr218Ser + Ser220Asp + Gly223Ser Ala204Gln + Ser207Asp + Trp208Gly + Ile209Ala + Thr212Asn + Ser220Glu + Gly223Pro Pro205Gln + Ser207Asp + Ile209Gln + Pro214Asn + Thr215Gln + Ser220Asp + Thr224Gly Pro205Asn + Ser207Glu + Ile209Val + Thr212Gly + Tyr213Pro + Ala219Asn + Thr224Glu Ala204Gly + Ser207Glu + Ile209Ala + Thr212Pro + Tyr213Cys + Ala219Glu + Ser220Asp Pro205Ser + Trp208Glu + Thr212Asn + Tyr218Glu + Ala219His + Leu221Glu + Ser222Glu Pro205Ser + Ile209Pro + Tyr210Asp + Thr212Ser + Tyr213Ile + Ala219Pro + Ser222Glu Gly206Ser + Trp208Thr + Tyr210Ala + Pro214Asp + Tyr218Met + Ala219Glu + Ser220Asp Ile209Leu + Pro214Glu + Thr215Pro + Ala219Glu + Ser220Glu + Gly223Pro + Thr224Gly Trp208Tyr + Thr212Asn + Thr217Glu + Ala219Gly + Ser220Asp + Leu221Glu + Ser222Asp Ala204Thr + Tyr210Pro + Tyr213Asn + Pro214Glu + Tyr218Asp + Ser220Asp + Thr224Gly Gly206Pro + Thr212Pro + Pro214Gly + Thr215Pro + Ser220Asp + Leu221Asp + Thr224Glu Thr212Asn + Pro214Gln + Tyr218Met + Ala219Asp + Ser222Glu + Gly223Asp + Thr224Glu Trp208Gly + Tyr210Pro + Thr212Gly + Ser220Glu + Leu221Met + Gly223Asp + Thr224Glu Gly206Gln + Tyr213Asn + Pro214Asn + Thr217Asp + Ala219His + Ser220Glu + Leu221Asp Pro205Gln + Ile209Pro + Tyr210Asn + Tyr218Thr + Ala219Glu + Ser220Asp + Gly223Asp Ala204Thr + Ser207Asp + Tyr210Asp + Tyr213Met + Ala219Asn + Ser220Glu + Thr224Asp Pro205Ser + Trp208Pro + Ile209Pro + Tyr213Ile + Ala219Asp + Ser222Asp + Gly223Asp Ala204Asn + Thr212Pro + Thr217Glu + Tyr218Asp + Ser220Glu + Ser222Asp + Thr224Gln Gly206Pro + Ser207Asp + Trp208Val + Tyr210Thr + Tyr213Ala + Ser220Asp + Thr224Asp Pro205Gly + Ser207Glu + Tyr210Ile + Pro214Ser + Thr217Gly + Ser220Asp + Thr224Glu Ala204Thr + Tyr210Cys + Thr212Pro + Tyr218Ile + Ser220Glu + Leu221Ser + Gly223Glu Ala204Gln + Trp208Pro + Pro214Asn + Ala219Thr + Ser220Glu + Gly223Asp + Thr224Gln Pro205Gln + Tyr213Gly + Thr215Gly + Tyr218Ala + Ser220Asp + Gly223Glu + Thr224Pro Pro205Gly + Gly206Ser + Thr217Pro + Ala219His + Ser220Asp + Leu221Cys + Gly223Asp Pro205Ser + Tyr210Thr + Thr212Asn + Tyr213Cys + Pro214Ser + Ala219Asp + Ser222Asp Trp208Asn + Thr217Glu + Tyr218Cys + Ala219Glu + Ser220Asp + Gly223Glu + Thr224Ser Pro205Ser + Gly206Pro + Trp208Pro + Ile209Ala + Thr215Asp + Tyr218Asp + Ser220Asp Trp208Thr + Thr212Gly + Tyr213Ile + Thr215Asp + Leu221Asp + Ser222Glu + Gly223Glu Ala204Gly + Pro205Gly + Tyr210Glu + Thr217Glu + Tyr218Cys + Ala219Gly + Leu221Val Ser207Asp + Thr215Pro + Thr217Asp + Tyr218Ile + Leu221Ala + Ser222Glu + Gly223Asp Gly206Pro + Trp208Glu + Tyr210Cys + Pro214Gln + Thr217Asp + Ser220Asp + Gly223Gln Trp208Thr + Tyr213Pro + Pro214Ser + Ser216Asp + Tyr218Met + Ala219Asp + Thr224Pro Ala204Asn + Trp208Ala + Tyr213Asn + Ser216Asp + Ala219Glu + Leu221Cys + Thr224Gly Gly206Ser + Tyr210Ser + Pro214Gly + Ser216Asp + Tyr218Cys + Ala219Glu + Leu221Pro Ala204Thr + Tyr210Gln + Thr212Gln + Tyr213Ala + Pro214Gln + Thr217Asp + Ser220Glu Pro205Gln + Gly206Ser + Ser207Glu + Tyr210Ser + Ser216Asp + Thr217Glu + Tyr218Glu Tyr210Met + Tyr213Met + Ser216Asp + Ala219Glu + Ser220Glu + Leu221Cys + Ser222Glu Ala204Gln + Ile209His + Ser216Glu + Thr217Ser + Ala219Glu + Ser220Asp + Ser222Glu Ile209Ser + Tyr210Leu + Tyr213Leu + Pro214Asp + Thr217Asp + Ser220Glu + Leu221Glu Ala204His + Pro205Gln + Pro214Asn + Tyr218Gln + Ala219Asp + Leu221Glu + Thr224Asp Ala204Gly + Ser207Glu + Pro214Glu + Tyr218Pro + Ser220Glu + Ser222Asp + Thr224Asn Ala204Pro + Pro205Gly + Trp208Glu + Ile209Ser + Tyr210Asp + Ala219Thr + Thr224Glu Ala204Gly + Ser207Glu + Trp208Glu + Tyr210Asp + Ser216Glu + Thr217Gln + Thr224Gly Trp208Ala + Tyr210Cys + Thr212Ser + Thr217Glu + Ala219Gln + Ser220Asp + Ser222Glu Gly206Asn + Ser207Glu + Trp208Glu + Thr212Ser + Ser216Glu + Leu221Met + Gly223Glu Ala204Thr + Ser207Asp + Ile209Cys + Thr215Asp + Tyr218Ile + Ser220Asp + Leu221Asp Ser207Asp + Thr212Pro + Pro214Gln + Ser216Glu + Tyr218Val + Ser220Asp + Ser222Asp Ile209Pro + Thr212Gly + Tyr213Ser + Pro214Glu + Thr215Glu + Ala219Gln + Ser220Glu Pro205Asn + Ser207Glu + Ile209Met + Pro214Ser + Ser216Asp + Ala219Glu + Leu221Asp Ala204Thr + Ser207Glu + Tyr210Leu + Ser216Glu + Ala219Asp + Leu221Asp + Gly223Asn Gly206Asn + Ser207Glu + Pro214Gly + Thr215Glu + Thr217Glu + Tyr218Thr + Ala219Glu Gly206Gln + Ser207Glu + Tyr210Ala + Thr215Asn + Thr217Asp + Ser220Asp + Leu221Ala Ser207Glu + Trp208Leu + Tyr213Val + Pro214Asp + Ala219Glu + Ser222Glu + Thr224Pro Ala204Thr + Ser207Asp + Trp208Leu + Tyr210Asp + Thr212Pro + Thr215Asp + Leu221Glu Pro205Gln + Ser207Asp + Ile209Ala + Thr217Asn + Tyr218Glu + Ala219Asp + Gly223Asp Ser207Glu + Ile209Thr + Tyr213Gly + Ser216Asp + Ala219Asp + Ser222Glu + Gly223Pro Gly206Ser + Ser207Asp + Ile209Ala + Thr212Gln + Thr217Glu + Ala219Glu + Leu221Asn Pro205Asn + Tyr210Glu + Thr217Asp + Tyr218Ala + Leu221Ile + Ser222Glu + Thr224Pro Ser216Asp + Thr217Asp + Tyr218Cys + Ala219His + Leu221Glu + Ser222Glu + Gly223Asn Ala204Gln + Trp208Asp + Pro214Gln + Ser216Glu + Thr217Gln + Ser220Asp + Gly223Asp Pro205Gln + Tyr210Leu + Tyr213Thr + Ser216Glu + Tyr218Glu + Ser220Glu + Gly223Glu Pro214Gly + Thr217Asp + Tyr218Gly + Ala219Glu + Leu221Asn + Ser222Glu + Thr224Glu Gly206Pro + Ser207Asp + Trp208Asp + Thr212Gln + Thr217Asp + Gly223Ser + Thr224Glu Ala204Pro + Pro205Ser + Gly206Pro + Ile209Val + Tyr213Pro + Thr215Asp + Ala219Glu Ala204Pro + Gly206Pro + Tyr210Val + Pro214Glu + Ser220Glu + Ser222Glu + Thr224Pro Ala204Gly + Gly206Pro + Thr212Gln + Pro214Glu + Ser220Glu + Leu221Val + Ser222Asp Ala204Asn + Gly206Gln + Ile209Ser + Tyr210Ala + Pro214Glu + Ser220Glu + Ser222Asp Pro205Gln + Trp208Gln + Pro214Glu + Thr217Pro + Leu221Met + Ser222Asp + Gly223Glu Ala204Thr + Pro205Asn + Pro214Asp + Thr215Pro + Leu221Cys + Ser222Asp + Gly223Asp Ile209Pro + Tyr210Pro + Thr212Pro + Thr217Asp + Leu221Asn + Ser222Asp + Gly223Asp Gly206Gln + Trp208Thr + Ile209Ser + Tyr213Met + Thr215Glu + Ser222Asp + Gly223Glu Pro205Asn + Trp208Ser + Thr212Gly + Tyr213Asn + Thr215Asp + Ser222Asp + Gly223Glu Tyr210Gly + Thr212Pro + Pro214Gly + Ser216Asp + Ala219His + Leu221Glu + Ser222Asp Pro205Gly + Gly206Pro + Ile209His + Thr215Asp + Ala219Gly + Leu221Glu + Ser222Glu Pro205Gln + Tyr210Gly + Thr212Asn + Ser216Asp + Ala219Pro + Ser220Glu + Leu221Asp Gly206Ser + Trp208Glu + Tyr210Gln + Thr215Gly + Ser216Glu + Thr217Glu + Leu221Pro Pro205Gln + Gly206Gln + Ser216Glu + Thr217Asp + Leu221Ala + Ser222Glu + Thr224Pro Gly206Ser + Ser207Glu + Trp208Asp + Ile209Leu + Thr215Asp + Ser216Glu + Tyr218Gln Tyr210His + Thr212Gln + Thr215Asp + Ser216Glu + Leu221Glu + Gly223Ser + Thr224Pro Ala204Ser + Pro205Ser + Gly206Asn + Thr215Asp + Ser216Glu + Tyr218Val + Gly223Asp Ala204Gln + Gly206Asn + Ser207Glu + Trp208Pro + Pro214Asp + Thr215Asp + Ser222Asp Ser207Asp + Tyr210Gln + Thr212Gln + Thr215Asp + Ser216Asp + Leu221Gly + Ser222Asp Ile209Met + Tyr210Leu + Thr217Glu + Tyr218Thr + Ser220Glu + Gly223Glu + Thr224Asn Pro205Ser + Ser207Glu + Trp208His + Thr215Pro + Thr217Asp + Leu221Asn + Ser222Glu Ala204Thr + Ser207Glu + Thr212Gly + Tyr213Leu + Pro214Asn + Ser216Glu + Ser222Glu Ala204Pro + Ser207Asp + Tyr210Leu + Thr212Gln + Tyr213Thr + Thr215Glu + Ser222Glu ...
Table 29
Polycyclic double mutant Leu104Gly + Tyr210Pro Asn 66Gln + Thr217Glu Gly 67Ser + Gly 69Ser Val103Gln + Gly223Asp Trp112Cys + Thr217Gly Ala164Glu + Trp208Gln Leu134Ile + Trp208Gln Ala219Gly + Ser220Glu Asn 66Asp + Leu104Gly Ala168Thr + Ser216Glu Leul04Ala + Ser109Glu Thr111Gln + Val115Ala Ser109Asp + Tyr210Pro Gly 69Ser + Serl91Asp Val103Asp + Gly206Gln Gly 67Glu + Pro214Asn Trp208Ile + Thr215Asp Ser107Glu + Thr113Gly Gly108Ser + Leu221Glu Ser 70Glu + Pro169Asn Gly165Gln + Leu221Asp Gly108Glu + Ala164Gly Leu104His + Thr167Pro Ala164His + Ser220Glu Thr195Gln + Ser222Asp Trp208His + Ala219Pro Gly 69Glu + Asn106Gln Trp112Cys + Thr113Pro Gly 67Gln + Trp208Asp Ala114Glu + Leu134Ile Ser109Glu + Gly136Ser Gly110Ser + Ser207Glu Val103Ala + Thr212Ser Ala114Glu + Thr167Pro Thr195Glu + Ala204Thr Gly 67Ser + Thr217Glu Trp208Tyr + Ser220Glu Ala168His + Thr217Asp Ala168Glu + Tyr213Asn Gly110Pro + Ser220Asp Tyr171Asn + Leu221Met Thr 73Asp + Leu134Ser Thr137Asn + Thr217Pro Ser 70Asp + Ala168Thr Thr167Glu + Tyr210Pro Thr195Glu + Tyr210Gly Tyr210Gln + Thr217Glu Gly 67Glu + Val115Cys Ser 70Glu + Ala219Thr Gly136Pro + Leu221Ala Gly 67Ser + Thr195Ser Phe193His + Ser222Asp Asn 68Glu + Tyr210Ser Gly165Asp + Pro169Ser Trp208Pro + Thr215Gly Thr 73Gly + Leu104Gly Thr113Asn + Ser216Glu Gly 72Gln + Gly139Asp Tyr210Ile + Leu221Gly Thr 73Pro + Tyr171Asp Leu104Gln + Thr137Gly Gly 69Pro + Tyr210Ala Thr217Gly + Gly223Glu Thr195Asp + Tyr213Ser Gly 72Asn + Ala219Asn Val138Pro + Tyr210Ala Tyr218Met + Gly223Asn Ser220Glu + Leu221Asn Trp112Ala + Gly139Asn Gly135Glu + Leu221Gly Thr113Asn + Thr217Ser Thr195Asn + Thr217Asp Tyr210Val + Ser220Glu Val138Gly + Ala219Asp Asn166Glu + Leu221His Gly165Gln + Leu221His Thr113Gln + Ser192Asp Asn 66Asp + Thr 73Ser Thr167Gln + Thr217Gly Val115Pro + Gly135Ser Ala219Gln + Gly223Asp Trp208His + Thr217Asn Trp208Leu + Tyr210Val Gly108Asn + Ser191Glu Ser107Glu + Tyr210Ala Asn 68Gln + Ser220Glu Trp112Cys + Leu221Asn Gly108Gln + Ser109Asp Val103Met + Ala168His Ala164Pro + Ser192Glu Pro214Ser + Ser220Glu Thr215Asn + Thr217Gln Ser220Glu + Leu221Pro Gly136Ser + Trp208Phe Thr195Asp + Tyr210Gln Leu104Gln + Ala219Asp Gly 69Pro + Leu221Pro Gly 69Asn + Ala204Gly Gly135Glu + Ala219Asn Gly136Asn + Ser220Glu Gly136Ser + Trp208Val Gly139Asp + Asn140Gln Trp208Cys + Tyr210Asn Gly165Ser + Ser220Asp Gly110Ser + Trp208Thr Ala114Asp + Gly162Asn Ser192Asp + Leu221Cys Val103Ser + Gly135Glu Asn140Glu + Trp208Ala Thr113Asp + Leu221Ser Ser109Asp + Gly110Ser Ser109Glu + Thr113Gln Thr 73Gly + Gly136Asp Ala164His + Leu221Asn Gly 67Pro + Va1103His Ala114Asn + Thr212Gln Asn140Asp + Gly223Pro Gly139Gln + Pro214Asn Asp105Glu + Thr195Gly Gly135Pro + Ser207Glu Leu104Glu + Ala114Pro Asn 66Glu + Gly 69Pro Val115Cys + Ser207Glu Asn 68Glu + Leu221Ala Asn 66Ser + Gly 69Asp Ser109Glu + Phe193Pro Trp208Glu + Thr212Pro Gly136Gln + Trp208Cys Ser 70Asp + Leu221His Ser 70Glu + Phe193Ser Thr217Asn + Ser222Glu Tyr213Thr + Tyr218Gly Trp208Ser + Leu221Cys Asn163Asp + Leu221Ser Asn 66Gln + Gly223Pro Gly139Asn + Ser220Asp Thr 73Ser + Pro214Asp Ser 70Asp + Leu221Ile Gly165Gln + Ser220Asp Asn166Asp + Thr217Asn Asp105Glu + Thr111Pro Asn140Asp + Trp208Phe Asn166Glu + Pro214Asn Trp208Ala + Thr217Ser Gly108Ser + Gly110Glu Val138Asn + Asn170Asp Gly110Glu + Thr224Gln Trp208Met + Ser220Asp Asn 68Glu + Val115Ser Asn170Glu + Tyr210Gly Gly110Asn + Ser192Glu Trp208Gln + Ser220Glu Asn140Gln + Pro214Gln Thr217Ser + Ser220Glu Ser141Glu + Ala168Thr Gly162Glu + Tyr210His Leu104Gly + Thr224Asp Trp112Pro + Ser191Asp Trp208Thr + Tyr210Glu Gly108Gln + Thr111Asp Leu134Val + Thr217Pro Asn170Asp + Tyr210His Val115Ser + Ser220Glu Gly 69Pro + Ser 70Asp Thr 73Gly + Tyr210Glu Gly 67Asp + Gly108Gln Gly 69Ser + Gly110Asp Tyr210Thr + Ser220Glu Trp208Phe + Leu221Met Gly136Gln + Leu221Asp Thr113Ser + Trp208Val Tyr171Leu + Tyr210Thr Leu134Asn + Thr167Gln Asn140Ser + Tyr210Asp Asn 66Gln + Gly 67Glu Leu134Cys + Pro214Asn Gly136Ser + Leu221Ala Thr111Pro + Trp208Val Thr113Asp + Tyr171Gly Trp208Ile + Ser220Glu Pro214Ser + Thr224Glu Gly165Pro + Ser220Glu Thr137Gln + Tyr171Glu TrP208Glu + Pro214Gly Ser216Asp + Leu221Met Gly136Ser + Thr217Gln Ser141Glu + Tyr210Leu Trp208Thr + Gly223Ser Asn 66Ser + Asn170Gln Asn 66Gln + Asn170Glu Pro169Glu + Tyr210Thr Tyr171Leu + Leu221Asp Gly139Glu + Leu221Pro Thr 73Pro + Leu134Gly Tyr210Glu + Leu221Ala Gly139Ser + Tyr210Gly Asn163Asp + Ala164Ser Asn163Gln + Thr217Asp Asn140Asp + Tyr218Ser Gly108Ser + Ala164Gln Val138Ser + Trp208Leu Thr217Ser + Thr224Asp Ser109Asp + Tyr218Ala Asn 66Glu + Phe193Val Asn140Asp + Ala204Gly Val138Ser + Ser220Asp Gly108Asn + Tyr210Thr Gly139Asn + Tyr171Pro Thr113Pro + Trp208Thr Ser141Glu + Leu221Gly Asn106Glu + Thr167Gly Trp112Ser + Ala219Ser Asp105Glu + Asn166Gln Ala114Pro + Tyr171Asn Thr217Gln + Ser220Asp Thr113Gly + Tyr210Asp Tyr171Cys + Tyr210Glu Asn166Asp + Leu221Val Ala114His + Ser191Asp Gly 67Glu + Thr217Asn Asn 66Glu + Thr215Gln Thr111Asn + Ser220Glu Trp208Gln + Leu221Ser Gly 69Gln + Ala114Thr Asn163Asp + Leu221Ala Pro214Gly + Leu221Ile Thr217Gly + Ser220Asp Ala219Thr + Ser220Asp Tyr210Cys + Ser220Glu Val138Asp + Gly223Pro Thr195Asn + Leu221Gly Leu104Thr + Thr215Ser Gly 69Gln + Leu134Thr Gly165Pro + Leu221Gly Thr167Ser + Thr217Glu Thr212Pro + Thr217Glu Asn166Ser + Tyr218Asp Gly108Glu + Tyr171Gln Gly 67Asn + Tyr210Ile Val115Cys + Pro214Gly Thr137Asp + Tyr210Val Leu104Met + Trp208Gly Leu134Ala + Ser192Asp Trp112Gln + Ala219Gln Gly108Glu + Val115His Thr113Asn + Gly139Pro Trp208Gln + Gly223Asn Ser207Glu + Trp208Gln Asn 66Ser + Tyr210Asn Ser207Glu + Tyr210Pro Val103Ala + Thr215Glu Val103Asn + Tyr210Ala Asn 66Ser + Trp208Phe Thr215Asn + Ala219Thr Gly136Asn + Gly139Asn Tyr171Thr + Ser216Glu Leu104Glu + Tyr210Asn Ser109Glu + Thr217Asn Leu134Ile + Asn166Ser Tyr171Gly + Thr217Gln Val115Cys + Thr224Asp Pro169Ser + Thr215Asp Gly 72Gln + Gly135Asn Tyr210Thr + Ser220Asp Asn 68Glu + Thr113Ser Asn106Gln + Thr113Asp Ser109Glu + Trp208Asn Leu134Gln + Thr137Glu Ala114Thr + Asn170Glu Ala219Pro + Ser220Glu Tyr171Val + Trp208Pro Gly139Ser + Tyr213Ser Ser107Asp + Thr113Asn Thr167Gly + Leu221Met Tyr171Gly + Ser207Glu Gly 67Ser + Thr217Ser Val115Gly + Thr217Ser Asn 66Ser + Trp208Ile Ser191Glu + Trp208Cys Thr137Asp + Trp208Ser Leu221Gly + Ser222Glu Ser216Glu + Leu221Thr Gly162Pro + Ser207Glu Thr217Asp + Ala219Thr Leu104Cys + Ser207Glu Gly 69Gln + Ser220Glu Gly 69Gln + Val138Asp Pro169Gly + Tyr210Leu Thr 73Asp + Gly110Ser Thr215Gly + Thr217Ser Gly 69Ser + Gly 72Asn Ser191Glu + Thr217Asn Gly135Ser + Tyr171Ser Thr111Asn + Phe193Leu Trp112Leu + Ser207Asp Leu104Glu + Trp208Ala Leu221Ile + Thr224Asp Gly136Glu + Gly165Asn Tyr210Glu + Thr217Pro Trp112Phe + Pro214Asp Gly110Gln + Trp112Met Asn 68Ser + Trp208Asp Gly 69Ser + Leu104Cys Thr137Glu + Thr215Pro Asn166Gln + Thr217Glu Tyr210Thr + Thr212Ser Leu134His + Trp208Asp Ser141Glu + Tyr210Val Ser191Glu + Tyr210Leu Gly139Pro + Ser207Asp Gly162Ser + Tyr171Met Thr 73Gln + Val103Ala Tyr171Val + Phe193Asp Leu221Thr + Ser222Glu Gly 69Asp + Ala114Gln Gly108Glu + Trp208Met Gly 72Ser + Tyr210Gln Thr137Asn + Trp208Asp Asn140Asp + Phe193Thr Ser192Glu + Trp208Ala Asn170Glu + Pro205Ser Tyr210Ala + Tyr213Ser Tyr171Gln + Tyr218Ile Asn 66Asp + Leu221Cys Asn163Gln + Gly223Asn Val103Thr + Leu134Ser Thr167Ser + Asn170Asp Ser 70Glu + Gly162Ser Tyr171Gln + Ser192Glu Tyr210Val + Gly223Ser Thr137Glu + Leu221Pro Gly 69Asn + Thr217Asp Pro205Ser + Tyr218Glu Tyr210Met + Leu221Asn Thr215Asp + Thr217Pro Leu134Val + Gly136Glu Thr 73Pro + Leu221Glu Tyr213Val + Ser220Glu Thr 73Ser + Ser107Glu Trp208Ser + Leu221Pro Thr113Asp + Leu221His Ala114Thr + Thr217Asp Ala168Ser + Tyr218Glu Trp208Asp + Leu221Asn Thr137Asp + Trp208Ile Gly135Gln + Ser191Glu Val103Glu + Trp208Gly Asn140Asp + Leu221His Ser192Asp + Tyr210Cys Gly108Asn + Tyr210His Asp105Glu + Trp208Asn Val103Pro + Tyr210Pro Thr 73Gln + Trp112Tyr Leu134Cys + Asn170Ser Asn166Glu + Tyr210Cys Asn106Ser + Leu221Met Ser109Glu + Leu221Cys Ser107Asp + Leu221Ala Ala114Ser + Leu221Asn Gly162Asn + Leu221Val ...
Table 33
Polycyclic three mutant Leu104Gly + Tyr210Pro + Thr217Glu Asn 66Gln + Gly 67Ser + Gly 69Ser Val103Gln + Trp112Cys + Gly223Asp Ala164Glu + Trp208Gln + Thr217Gly Leu134Ile + Trp208Gln + Ser220Glu Asn 66Asp + Leu104Gly + Ala219Gly Leu104Ala + Thr111Gln + Val115Ala Gly 69Ser + Ser109Asp + Tyr210Pro Gly139Asn + Thr167Asn + Thr217Ser Gly108Glu + Ala164Gly + Gly165Gln Leu104His + Thr167Pro + Ser220Asp Gly 69Glu + Asn106Gln + Trp208His Trp112Cys + Thr113Pro + Trp208Asp Gly110Ser + Ser207Glu + Thr212Ser Ala168His + Trp208Tyr + Ser220Glu Tyr171Asn + Thr217Asp + Leu221Met Ser 70Asp + Thr137Asn + Thr217Pro Thr167Glu + Ala168Thr + Tyr210Pro Ser 70Glu + Gly136Pro + Leu221Ala Gly 67Ser + Thr195Ser + Ser222Asp Pro169Ser + Trp208Pro + Thr215Gly Thr 73Gly + Leu104Gly + Tyr171Glu Gly 72Gln + Tyr210Ile + Leu221Gly Leu104Gln + Thr137Gly + Tyr210Ala Tyr213Ser + Thr217Gly + Gly223Glu Gly 72Asn + Thr195Asp + Ala219Asn Thr137Asp + Val138Pro + Tyr210Ala Ser109Glu + Val115Met + Trp208Cys Gly139Asn + Ser220Glu + Leu221Asn Trp112Ala + Gly135Glu + Leu221Gly Thr113Asn + Thr195Asn + Thr217Ser Ala164His + Ser220Asp + Leu221His Asn 66Asp + Thr 73Ser + Thr113Gln Gly135Ser + Thr167Gln + Thr217Gly Tyr171Asp + Trp208His + Thr217Asn Gly108Asn + Trp208Leu + Tyr210Val Trp112Cys + Ser220Glu + Leu221Asn Val103Met + Ala168His + Ser191Asp Pro214Ser + Thr217Gln + Ser220Glu Thr215Asn + Ser220Glu + Leu221Pro Gly136Ser + Trp208Phe + Tyr210Gln Gly 69Pro + Ala219Asp + Leu221Pro Gly 69Asn + Ala204Gly + Ser220Asp Gly136Ser + Gly139Asp + Trp208Val Asn140Gln + Trp208Cys + Tyr210Asn Gly110Ser + Gly165Ser + Trp208Thr Val103Ser + Gly135Glu + Leu221Cys Asn140Glu + Trp208Ala + Leu221Ser Gly 67Pro + Val103His + Ala164His Asn140Asp + Thr212Gln + Gly223Pro Gly139Gln + Thr195Gly + Pro214Asn Gly 69Pro + Leu104Glu + Ala114Pro Phe193Pro + Trp208Glu + Thr212Pro Gly136Gln + Trp208Cys + Leu221His Ser 70Asp + Thr 73Gly + Phe193Ser Tyr213Thr + Tyr218Gly + Gly223Asp Thr195Glu + Trp208Ser + Leu221Cys Asn163Asp + Leu221Ser + Gly223Pro Asn 66Gln + Gly139Asn + Ser220Asp Thr 73Ser + Pro214Asp + Leu221Ile Thr111Pro + Asn140Asp + Trp208Phe Asn166Glu + Pro214Asn + Thr217Ser Gly108Ser + Gly110Glu + Trp208Ala Leu134Asp + Gly165Asn + Tyr210Thr Phe193Thr + Thr217Gln + Ser220Asp Gly 67Pro + Trp112Gln + Ser192Asp Tyr210Ile + Thr217Gln + Ser222Asp Val103Ser + Leu104Ile + Ala164Asn Ala114Asp + Thr167Gly + Thr217Asn Thr111Asp + Thr195Gly + Tyr210Leu Tyr210Thr + Ser220Glu + Leu221Met Gly136Gln + Trp208Phe + Leu221Asp Thr113Ser + Trp208Val + Tyr210Thr Leu134Asn + Asn140Ser + Thr167Gln Gly136Ser + Trp208Val + Leu221Ala Gly165Pro + Pro214Ser + Ser220Glu Gly136Ser + Tyr210Leu + Thr217Gln Ser141Glu + Trp208Thr + Gly223Ser Asn 66Ser + Thr113Pro + Asn170Glu Thr 73Pro + Tyr210Thr + Ser216Glu Thr 73Pro + Tyr210Glu + Leu221Ala Gly139Ser + Ala164Ser + Tyr210Gly Gly108Ser + Val138Ser + Ala164Gln Trp208Leu + Thr217Ser + Thr224Asp Asn 66Glu + Phe193Val + Tyr218Ala Gly108Asn + Tyr171Pro + Tyr210Thr Thr113Pro + Gly139Asn + Trp208Thr Asp105Glu + Asn166Gln + Tyr171Asn Ala114Pro + Thr217Gln + Ser220Asp Gly 67Glu + Ala114His + Thr217Asn Ser141Glu + Trp208Gln + Leu221Ser Gly 69Gln + Ala114Thr + Asn170Asp Asn163Asp + Ala219Thr + Leu221Ala Ser 70Asp + Thr217Gly + Ala219Thr Thr195Asn + Leu221Gly + Gly223Pro Gly 69Gln + Leu104Thr + Leu134Thr Gly139Asp + Gly165Pro + Leu221Gly Gly 67Asn + Gly108Glu + Tyr210Ile Val115Cys + Tyr210Val + Pro214Gly Leu104Met + Thr137Asp + Trp208Gly Trp112Gln + Leu134Ala + Ser192Asp Gly108Glu + Val115His + Ala219Gln Thr113Asn + Gly139Pro + Thr167Asp Thr137Asp + Trp208Gln + Gly223Asn Ser207Glu + Trp208Gln + Tyr210Asn Asn 66Ser + Ser207Glu + Tyr210Pro Val103Asn + Tyr210Ala + Thr215Glu Asn 66Ser + Trp208Phe + Ala219Thr Gly136Asn + Gly139Asn + Thr215Asn Ser109Glu + Asn166Ser + Thr217Asn Leu134Ile + Tyr171Gly + Thr217Gln Gly 72Gln + Gly110Asp + Gly135Asn Asn 68Glu + Asn106Gln + Thr113Ser Ala114Thr + Leu134Gln + Thr137Glu Ser107Asp + Gly139Ser + Tyr213Ser Thr113Asn + Thr167Gly + Leu221Met Gly 67Ser + Ser207Glu + Thr217Ser Asn 66Ser + Trp208Ile + Thr217Ser Trp208Ser + Leu221Gly + Ser222Glu Gly162Pro + Ser216Glu + Leu221Thr Leu104Cys + Asn106Gln + Ser207Glu Gly 69Gln + Pro169Gly + Tyr210Leu Thr 73Asp + Gly110Ser + Thr217Ser Gly 69Ser + Gly 72Asn + Thr215Gly Gly135Ser + Tyr171Ser + Ser191Glu Thr111Asn + Phe193Leu + Thr217Glu Trp208Ala + Leu221Ile + Thr224Asp Trp112Phe + Pro214Asp + Thr217Pro Asn 68Ser + Gly110Gln + Trp112Met Gly 69Ser + Leu104Cys + Trp208Asp Thr137Glu + Asn166Gln + Thr215Pro Gly108Glu + Tyr210Thr + Thr212Ser Thr 73Gln + Gly162Ser + Tyr171Met Tyr171Val + Phe193Asp + Leu221Thr Gly 72Ser + Gly108Glu + Trp208Met Thr137Asn + Trp208Asp + Tyr210Gln Asn140Asp + Phe193Thr + Trp208Ala Gly 69Glu + Tyr210Ala + Tyr213Ser Asn 66Asp + Tyr218Ile + Leu221Cys Val103Thr + Leu134Ser + Asn163Gln Tyr171Gln + Ser192Glu + Gly223Ser Gly 69Asn + Thr137Glu + Leu221Pro Pro205Ser + Tyr218Glu + Leu221Asn Tyr210Met + Thr215Asp + Thr217Pro Thr 73Pro + Leu134Val + Gly136Glu Thr 73Ser + Ser107Glu + Trp208Ser Gly162Gln + Ser220Asp + Leu221Pro Val103Glu + Gly135Gln + Trp208Gly Asn140Asp + Tyr210Cys + Leu221His Gly108Asn + Ser192Asp + Tyr210His Asp105Glu + Trp208Asn + Tyr210Pro Thr 73Gln + Val103Pro + Trp112Tyr Leu134Cys + Asn170Ser + Tyr210Cys Asn106Ser + Ser109Glu + Leu221Cys Ser107Asp + Ala114Ser + Leu221Ala Gly 69Asn + Gly162Asn + Leu221Asn Gly 67Ser + Gly135Asp + Gly162Asn Val115Gly + Leu134Ser + Ala164Gln Asn 66Glu + Leu104Asn + Ala168Gly Gly 69Ser + Asn166Glu + Tyr218Asn Thr113Asp + Ala204Ser + Tyr218Ser Asn166Gln + Trp208Thr + Thr217Asp Gly108Glu + Thr217Ser + Tyr218Gly Asn106Asp + Trp208Met + Thr217Gln Gly 69Glu + Tyr171Val + Trp208His Gly139Asn + Pro169Gly + Trp208Asn Val115Ala + Thr215Gln + Leu221Glu Thr111Pro + Pro169Gln + Ala219Glu Thr 73Glu + Thr137Asn + Trp208His Asn 66Asp + Asn106Ser + Leu221Thr Gly 67Pro + Gly 69Ser + Thr224Ser Val115His + Ser191Asp + Tyr218Val Thr137Glu + Thr195Asn + Trp208Gly Leu134Glu + Trp208Ser + Leu221Ser Val103Ser + Trp208Glu + Thr217Asn Gly139Asn + Phe193Pro + Leu221Cys Asn106Gln + Ala164Pro + Asn166Asp Asp105Glu + Val138Ser + Thr217Pro Gly135Pro + Tyr171Thr + Ser222Glu Ser216Asp + Thr217Asn + Thr224Gly Ala114Gly + Asn140Gln + Tyr218Asp Ser107Asp + Pro214Gly + Leu221Ser Asp105Glu + Asn170Ser + Thr195Pro Ser 70Glu + Tyr171Leu + Pro214Ser Gly 67Asp + Leu104Thr + Gly223Asn Gly108Asp + Ala114Asn + Tyr210Cys Gly110Asn + Pro214Gly + Ser220Asp Gly 69Asn + Pro169Gln + Ser220Glu Gly162Glu + Trp208Ala + Thr217Asn Trp112Tyr + Val115Pro + Ser220Glu Trp208Gly + Tyr210Ile + Pro214Asp Leu134Asn + Pro169Ser + Leu221Asp Thr113Ser + Trp208Leu + Leu221Glu Asn166Ser + Tyr218Ile + Ser220Glu Trp112Pro + Phe193His + Pro214Asp Leu104Glu + Val115Ser + Ala164Ser Gly 69Pro + Pro169Asp + Leu221His Gly108Gln + Val138Ser + Ser220Glu Gly110Asn + Thr137Gln + Ser220Glu Ala164Thr + Asn166Ser + Tyr210Asp Trp112Pro + Val115Pro + Pro214Glu Val115Glu + Gly139Asn + Tyr210Gln Gly 69Ser + Thr 73Ser + Tyr210Pro Ala114Ser + Ser207Asp + Thr224Pro Thr 73Pro + Asn166Glu + Thr212Gly Gly 72Gln + Gly110Asp + Leu221His Tyr210Cys + Pro214Asn + Tyr218Asp Gly 69Asn + Gly136Pro + Asn166Ser Thr 73Gly + Gly108Ser + Ser220Glu Thr 73Gly + Pro205Ser + Thr224Ser Val103Met + Ala164Asp + Leu221Met Thr111Asn + Thr167Glu + Phe193Met Thr 73Asp + Tyr210Asn + Thr217Gln Asn 66Glu + Thr 73Gly + Leu221Gln Thr113Asp + Asn166Ser + Thr167Pro Asn 66Gln + Tyr171Gly + Tyr210Pro Asn 68Ser + Gly 69Pro + Asn170Gln Asn 68Ser + Val115Glu + Tyr210Asn Thr113Gln + Ser191Asp + Leu221His Thr167Pro + Trp208Val + Tyr210Leu Gly162Glu + Trp208Ala + Thr217Pro Leu104Met + Ser207Asp + Thr212Gly Thr137Gln + Asn163Asp + Pro205Gln Val115Thr + Thr217Gln + Ser220Asp Ser 70Asp + Val138Ser + Tyr210Val Pro214Gly + Leu221Ile + Thr224Asp Leu134Val + Gly165Gln + Trp208Thr Ser109Asp + Ala114Asn + Tyr210Ser Asn 66Ser + Val115Asn + Trp208Gln Thr 73Pro + Phe193Glu + Gly206Gln Leu134Ser + Leu221Pro + Ser222Asp Val115Cys + Ala164Glu + Asn170Gln Ala164Asn + Trp208Cys + Thr217Glu Asn 66Glu + Ala168Pro + Thr215Pro Gly135Ser + Ser207Asp + Thr217Gln Asn140Gln + Thr167Asp + Trp208Met Gly165Gln + Trp208Thr + Leu221Asn Thr 73Pro + Asn106Glu + Leu221Cys Thr113Ser + Leu221Ile + Gly223Asp Asn 66Asp + Gly136Gln + Gly162Gln Ser191Glu + Thr217Asn + Thr224Pro Leu104Gln + Gly162Glu + Tyr210Gln Trp112Gln + Asn163Asp + Thr217Gly Leu134Pro + Thr217Asn + Leu221Glu Gly165Pro + Tyr210Met + Thr217Glu Ala164Gly + Ser191Glu + Trp208Cys Val115Cys + Gly139Asn + Pro205Asn Gly135Pro + Trp208Ala + Tyr210Pro Pro169Asn + Thr195Glu + Tyr210His Ser107Asp + Trp208Met + Tyr210Pro Thr 73Gly + Ala164Gly + Tyr210Glu Leu104Val + Pro205Gln + Leu221Asp Thr111Gln + Ser141Asp + Leu221Asn Trp112Cys + Thr167Gln + Thr217Pro Val138Thr + Asn170Glu + Leu221Pro Ser 70Asp + Leu134Ser + Thr224Asn Thr137Asn + Ser207Asp + Tyr218Thr Gly135Glu + Ala164Asn + Ala203Ser Leu134Gly + Trp208Glu + Thr212Ser Asn163Asp + Trp208Asn + Tyr210Thr Val115Thr + Ser192Glu + Thr217Ser Gly 72Pro + Ser109Asp + Tyr210Gln Ser109Glu + Asn163Gln + Phe193Pro Gly136Pro + Pro169Glu + Leu221Ser Gly110Asn + Ser220Glu + Leu221Met Trp112Gly + Tyr210Asp + Thr217Pro Trp208Ser + Tyr210Ser + Leu221Pro Trp112Met + Ser192Glu + Leu221Ala Thr137Gly + Thr167Ser + Thr217Glu Ser109Asp + Gly162Pro + Tyr210Ala Ala114Thr + Gly162Asn + Ser191Glu Thr195Asn + Tyr218Pro + Leu221Glu Thr 73Glu + Ala164Gln + Pro214Ser Asn 68Glu + Trp208Tyr + Thr217Asn Gly165Pro + Thr212Ser + Ser220Glu Gly 67Asn + Gly139Gln + Ala168Asp Ser141Glu + Pro214Gln + Leu221Gln Gly206Ser + Trp208Tyr + Thr215Gln Leu134Pro + Gly162Asn + Phe193Ile Trp112Ala + Thr217Asn + Ser220Asp Thr111Gly + Gly139Glu + Thr212Asn Ser107Glu + Tyr213Ala + Thr217Pro Gly165Ser + Thr217Glu + Gly223Pro Tyr210His + Thr217Asp + Leu221Ala Trp208Cys + Thr217Asp + Tyr218Asn Gly 69Gln + Val103Ala + Ser220Glu Asn106Ser + Tyr210Gly + Gly223Ser Trp208Cys + Tyr210Asn + Thr217Asp Asn 66Gln + Gly139Gln + Thr217Gly Thr 73Glu + Leu104Ile + Tyr210Ile Thr113Ser + Pro169Asn + Thr217Ser Tyr210Gly + Pro214Gly + Leu221Glu Leu134Ile + Ala219Glu + Ser220Asp Asn140Asp + Ser141Glu + Tyr218Ser Tyr213Val + Ser220Glu + Leu221Glu Tyr210Val + Ser220Glu + Leu221Asp Ala164His + Ser220Glu + Leu221Glu Tyr171His + Ser220Asp + Leu221Glu Tyr210Ile + Ser220Glu + Leu221Asp Trp112Leu + Ser220Asp + Leu221Glu Gly136Pro + Ser191Asp + Ser192Glu Ala168Ser + Thr217Asp + Tyr218Glu Asn166Ser + Thr217Glu + Tyr218Asp Gly162Asp + Asn163Glu + Leu221Met Trp208Ser + Tyr210Glu + Ser220Asp Ala114Thr + Gly165Asp + Phe193Glu Ser207Glu + Thr217Asn + Ser222Glu Asn140Ser + Trp208Glu + Ser220Asp Trp208Asp + Leu221Asn + Ser222Glu Gly139Gln + Trp208Glu + Leu221Asp Asn 68Glu + Asp105Glu + Asn106Asp Thr137Gln + Gly139Asp + Tyr171Glu Trp208Asp + Tyr210Glu + Leu221Ala Gly 69Pro + Asn166Glu + Ala168Glu Tyr171Cys + Tyr210Glu + Leu221Asp Thr137Glu + Pro169Asp + Asn170Ser Gly162Glu + Tyr171Asp + Thr217Ser Leu134Ile + Ser191Glu + Gly223Glu Val115Pro + Ser207Glu + Ser220Asp Gly139Pro + Ser207Asp + Ser220Glu Ser 70Glu + Val103Pro + Asn106Asp Gly 69Asp + Thr 73Asp + Tyr218Ile Asn 66Asp + Trp208Gly + Pro214Glu Asn 66Asp + Ser 70Glu + Gly136Ser Asn163Asp + Ser191Asp + Ser207Glu Asn 66Ser + Gly 69Asp + Ser109Glu Gly 67Glu + Trp208Ile + Thr215Asp Ser 70Glu + Tyr210Gln + Thr217Glu Ser 70Glu + Gly135Pro + Thr217Glu Val138Glu + Ser141Asp + Tyr210Gln Val138Glu + Ser141Glu + Pro214Asn Ser107Asp + Gly110Asp + Ala114Glu Ser109Glu + Ala114Glu + Gly136Ser Gly110Glu + Gly136Glu + Tyr210Gln Gly135Ser + Tyr210Asp + Thr217Glu Ser 70Glu + Pro169Asn + Leu221Asp Val115Gly + Gly162Asp + Thr167Asp Gly110Pro + Thr217Asp + Ser220Asp Ala164His + Thr217Asp + Ser220Asp Tyr210Cys + Thr217Asp + Ser220Asp Val103Ser + Thr217Asp + Ser220Asp Thr217Glu + Tyr218Val + Ser220Glu Gly 69Ser + Thr217Glu + Ser220Glu Tyr210Val + Thr217Asp + Ser220Glu Gly 67Glu + Ser107Glu + Thr111Asn Asn166Asp + Ser191Asp + Leu221Val Leu134Asp + Phe193Glu + Gly223Asp Asn 66Asp + Ser216Asp + Thr217Glu Val103Glu + Asn106Glu + Thr113Glu Ser 70Asp + Gly139Ser + Ser220Asp Leu104Asp + Asp105Glu + Ser191Glu Ala114Glu + Ser216Asp + Thr217Glu Thr195Glu + Ser216Asp + Thr217Glu Val115Glu + Ser220Asp + Leu221Glu Ser109Asp + Ser220Asp + Leu221Glu Thr215Glu + Ser216Asp + Ser220Asp Ser192Asp + Phe193Glu + Thr217Asp Gly165Asp + Tyr210Glu + Ser220Asp Ser 70Glu + Asp105Glu + Tyr218Asp Gly 69Glu + Ala168Glu + Thr195Glu ...
Table 34
Polycyclic four mutant Asn 66Gln + Leu104Gly + Tyr210Pro + Thr217Glu Gly 67Ser + Gly 69Ser + Val103Gln + Gly223Asp Trp112Cys + Ala164Glu + Trp208Gln + Thr217Gly Leu134Ile + Trp208Gln + Ala219Gly + Ser220Glu Leu104Ala + Ser109Glu + Thr111Gln + Val115Ala Gly108Glu + Ala164Gly + Gly165Gln + Thr167Pro Gly 69Glu + Asn106Gln + Trp112Cys + Thr113Pro Thr 73Asp + Leu134Ser + Thr137Asn + Thr217Pro Gly 67Ser + Gly136Pro + Thr195Ser + Leu221Ala Thr 73Gly + Leu104Gly + Trp208Pro + Thr215Gly Gly110Glu + Gly136Pro + Phe193Met + Thr217Pro Ala164Gln + Tyr171Ile + Phe193Ile + Thr224Gly Gly136Pro + Ala164Thr + Ser207Asp + Trp208Leu Gly108Gln + Trp112Pro + Trp208Thr + Tyr210Glu Thr111Asp + Leu134Val + Tyr210His + Thr217Pro Gly136Gln + Trp208Phe + Ala219Asp + Leu221Met Thr113Ser + Tyr171Leu + Trp208Val + Tyr210Thr Gly136Ser + Ser141Glu + Trp208Thr + Tyr210Leu Asn 66Ser + Thr 73Pro + Thr113Pro + Asn170Glu Thr 73Pro + Gly139Ser + Tyr210Glu + Leu221Ala Gly108Ser + Val138Ser + Trp208Leu + Thr217Ser Asn 68Ser + Gly110Gln + Trp112Met + Ser192Asp Thr 73Gln + Val103Ala + Gly162Ser + Ala164Glu Thr137Asn + Asn140Asp + Phe193Thr + Trp208Ala Leu134Ser + Asn163Gln + Ser220Glu + Gly223Asn Asn140Glu + Tyr171Gln + Tyr210Val + Gly223Ser Thr 73Pro + Leu134Val + Gly136Glu + Thr217Pro Ser107Glu + Gly162Gln + Trp208Ser + Leu221Pro Gly108Asn + Gly162Asn + Ser192Asp + Tyr210Cys Val103Pro + Ser109Glu + Trp208Asn + Tyr210Pro Thr 73Gln + Trp112Tyr + Leu134Cys + Asn170Ser Gly 69Asn + Gly162Asn + Asn166Ser + Leu221Asn Gly 67Ser + Leu134Ser + Gly162Asn + Ala164Gln Leu134Ile + Gly135Pro + Ala168Thr + Trp208Met Trp112Ser + Ala168His + Thr217Ser + Leu221Ala Gly110Ser + Thr111Gln + Thr215Ser + Ser222Asp Thr111Pro + Thr137Asn + Pro169Gln + Ala219Glu Thr 73Glu + Asn106Ser + Trp208His + Leu221Thr Asn 66Asp + Gly 67Pro + Gly 69Ser + Thr224Ser Leu104Cys + Val115His + Ser191Asp + Tyr218Val Leu134Glu + Thr195Asn + Trp208Ser + Leu221Ser Val103Ser + Gly139Asn + Thr217Asn + Leu221Cys Asn106Gln + Ala164Pro + Asn166Asp + Phe193Pro Asp105Glu + Gly135Pro + Val138Ser + Thr217Pro Gly 67Asp + Thr113Asn + Ala114Asn + Tyr210Cys Asn166Asp + Thr195Gly + Tyr210Gly + Thr224Gln Trp112Pro + Asn166Ser + Phe193His + Tyr218Ile Gly 69Pro + Leu104Glu + Val115Ser + Ala164Ser Trp112Pro + Val115Glu + Gly139Asn + Tyr210Gln Gly 69Ser + Thr 73Ser + Tyr210Pro + Thr224Pro Gly 72Gln + Thr 73Pro + Gly110Asp + Leu221His Thr111Asn + Gly136Pro + Tyr210Thr + Tyr218Asp Gly108Asp + Gly136Asn + Asn166Ser + Leu221Thr Val103Met + Pro205Ser + Leu221Met + Thr224Ser Gly 69Asn + Thr 73Asp + Trp208Gln + Tyr210Leu Thr 73Gly + Asn166Ser + Thr167Pro + Leu221Gln Asn 66Gln + Thr113Asp + Tyr171Gly + Tyr210Pro Gly162Glu + Thr167Pro + Trp208Val + Tyr210Leu Ser207Asp + Trp208Ala + Thr212Gly + Thr217Pro Leu104Met + Thr137Gln + Asn163Asp + Pro205Gln Ser109Asp + Leu134Val + Gly165Gln + Trp208Thr Ala114Asn + Val115Asn + Trp208Gln + Tyr210Ser Asn 66Glu + Ala164Asn + Trp208Cys + Thr215Pro Gly135Ser + Ala168Pro + Ser207Asp + Thr217Gln Thr167Asp + Trp208Met + Thr217Gln + Leu221Asn Thr 73Pro + Asn106Glu + Thr113Ser + Leu221Cys Gly162Gln + Ser191Glu + Thr217Asn + Thr224Pro Gly 69Gln + Leu104Gln + Gly162Glu + Tyr210Gln Leu104Gln + Tyr171Pro + Thr217Gly + Leu221Glu Gly110Glu + Phe193Asn + Trp208Cys + Gly223Pro Ala164Gly + Ser191Glu + Pro205Asn + Trp208Cys Gly135Pro + Ser207Glu + Trp208Ala + Tyr210Cys Thr 73Glu + Leu104Val + Pro205Gln + Leu221Cys Trp112Cys + Val138Thr + Thr167Gln + Thr217Pro Ser109Asp + Ala164His + Gly223Pro + Thr224Asn Asn 68Gln + Tyr210Pro + Thr212Ser + Ser220Asp Leu134Gly + Trp208Glu + Tyr210Met + Thr212Ser Asn163Asp + Asn170Gln + Trp208Asn + Tyr210Thr Trp112Gly + Trp208Ser + Tyr210Asp + Thr217Pro Trp112Met + Ser192Glu + Trp208Ser + Tyr210Val Trp112Leu + Ser220Asp + Leu221Ala + Thr224Asn Leu104Met + Thr111Asp + Ala164Gln + Pro214Ser Gly139Gln + Gly165Pro + Thr212Ser + Ser220Glu Thr113Asp + Leu134His + Trp208Ile + Leu221Ala Asp105Glu + Pro214Gln + Thr215Gln + Leu221Gln Leu134Pro + Gly162Asn + Gly206Ser + Trp208Tyr Trp112Ala + Phe193Ile + Thr217Asn + Ser220Asp Ser107Glu + Thr212Asn + Tyr213Ala + Thr217Pro Gly 67Gln + Gly 69Gln + Thr113Asn + Ser220Glu Asn 66Gln + Trp208Cys + Tyr210Asn + Thr217Asp Thr 73Glu + Leu104Ile + Gly139Gln + Thr217Gly Thr113Ser + Pro169Asn + Tyr210Ile + Thr217Ser Leu134Pro + Thr167Gln + Tyr210Met + Ser220Asp Thr 73Glu + Asn166Gln + Tyr171His + Leu221Ala Val138Met + Asn170Gln + Thr217Asn + Ala219His Gly136Gln + Ala219Ser + Ser220Asp + Thr224Gln Gly 69Asn + Asn166Gln + Tyr210Glu + Thr217Gly Thr 73Ser + Gly165Gln + Thr212Pro + Ser222Glu Thr137Pro + Asn140Gln + Tyr171Gly + Ser220Glu Tyr210Pro + Tyr213Ile + Ser220Asp + Leu221Pro Val103Asp + Asn106Ser + Phe193His + Thr217Gly Asn 68Asp + Thr113Asn + Val138Ala + Trp208His Asp105Glu + Leu134Met + Gly165Ser + Leu221Gln Asn 68Gln + Trp208Thr + Thr217Ser + Ser220Asp Tyr171Asn + Thr195Asn + Tyr210Asn + Tyr218Asn Asn 66Ser + Pro169Ser + Tyr210Cys + Gly223Glu Ala114Gln + Phe193Glu + Tyr210Gly + Thr224Pro Asn 66Ser + Gly136Ser + Ala164Asp + Ala168Gln Leu104Gly + Gly162Pro + Ser192Asp + Leu221Asn Gly108Asp + Gly162Pro + Trp208Thr + Gly223Asn Asn 66Glu + Thr113Gly + Ala164Pro + Gly223Pro Gly110Pro + Trp112Ala + Ser216Glu + Leu221His Val115Met + Pro169Ser + Trp208His + Tyr210Asp Leu104Ser + Ser109Asp + Gly110Pro + Thr195Gly Leu104Asn + Thr137Glu + Trp208Ser + Leu221Val Asn106Gln + Ala114Asp + Tyr171Thr + Leu221Pro Pro205Asn + Tyr210Asn + Thr217Gly + Tyr218Leu Leu104Pro + Asn106Ser + Thr137Asp + Thr217Pro Gly110Ser + Thr137Gln + Asn170Glu + Thr217Asn Thr113Gly + Phe193Met + Trp208His + Tyr213Ile Asn166Gln + Ser207Asp + Thr217Ser + Tyr218Met Gly162Asp + Phe193Pro + Trp208Tyr + Thr217Gln Gly 69Ser + Ser107Glu + Trp208Met + Tyr210Leu Val103Asp + Thr167Pro + Ile209Val + Tyr210Gln Thr111Asn + Asn170Ser + Trp208Tyr + Thr212Gly Ser107Glu + Thr137Pro + Gly162Ser + Trp208Cys Val103Thr + Ala164Thr + Ala168Glu + Thr217Ser Gly139Pro + Tyr210Asn + Leu221Pro + Thr224Pro Leu134Ser + Ser141Glu + Tyr210Ala + Thr217Gln Val103Asn + Leu134Ala + Tyr218Met + Thr224Asn Asn 66Asp + Gly135Gln + Asn163Ser + Leu221Val Gly 69Glu + Val115Pro + Thr137Pro + Trp208Ile Gly 69Pro + Gly165Pro + Tyr210Ser + Leu221Ile Asn 66Gln + Gly110Glu + Trp112Gly + Trp208Pro Trp112Ala + Ala114Pro + Gly135Ser + Asn163Asp Gly 67Asn + Ser207Glu + Tyr210Thr + Thr217Pro Asn166Asp + Thr167Pro + Ile209His + Tyr210Val Thr 73Ser + Asn106Gln + Tyr171Glu + Thr217Asn Val115Glu + Tyr210Ser + Thr217Gln + Ala219Gly Leu104Pro + Thr195Gln + Trp208Tyr + Ser222Asp Ser141Asp + Ala204Gln + Trp208Val + Tyr210Leu Gly 67Ser + Gly 69Glu + Val103Gly + Tyr210Gln Tyr171Met + Phe193Leu + Thr215Asp + Thr217Gln Asn 68Gln + Asp105Glu + Trp208Phe + Leu221Ala Leu104Asn + Val115Gln + Leu134Gln + Pro214Glu Gly165Ser + Ser191Asp + Pro214Gly + Leu221Thr Gly 67Ser + Asn 68Gln + Tyr210Val + Ser220Asp Ser109Asp + Val138Gly + Trp208Ser + Thr217Pro Thr111Gly + Gly136Pro + Ser141Asp + Leu221Ile Trp112Asn + Gly162Ser + Ile209Cys + Thr224Gln Val115Ala + Pro169Glu + Tyr210Val + Leu221Cys Gly135Ser + Tyr210Leu + Thr217Glu + Leu221Pro Asn 66Gln + Ser109Asp + Gly110Gln + Tyr218Thr Thr 73Gly + Trp208Ile + Thr217Glu + Leu221Asn Leu134Ser + Trp208His + Tyr210Leu + Ser220Glu Gly135Pro + Thr137Gln + Ala219Ser + Leu221Gln Asn 68Gln + Asn106Glu + Pro169Gln + Thr215Gln Val138Gln + Gly165Glu + Tyr218Leu + Leu221Cys Phe193Gln + Ser207Asp + Trp208Cys + Thr217Gln Gly 67Asn + Gly165Asn + Phe193Tyr + Pro205Ser Asn 66Ser + Ala168Ser + Tyr210Cys + Thr217Asp Pro214Gly + Ser216Asp + Thr217Gln + Leu221His Asn 66Gln + Val115Gln + Asn166Asp + Tyr218Met Thr111Glu + Gly165Ser + Ala219His + Leu221Thr Ser141Asp + Asn163Ser + Phe193Tyr + Ala204Ser Gly108Pro + Asn163Ser + Gly165Asp + Tyr213Ser Trp208His + Tyr210Thr + Tyr218Gln + Ser220Asp Gly 69Glu + Ala164Pro + Trp208Val + Thr224Ser Ser109Asp + Ala203Pro + Trp208His + Thr217Ser Thr 73Asp + Tyr171Cys + Tyr210Pro + Leu221Pro Gly162Pro + Tyr218Val + Ala219Thr + Ser220Glu Asn170Gln + Ser192Glu + Trp208Pro + Tyr210Gly Thr113Ser + Thr137Gln + Phe193Ser + Pro205Ser Trp112Pro + Thr137Gly + Ser220Asp + Leu221Asn Gly162Glu + Ala164Ser + Ala168His + Pro214Asn Ala114Pro + Leu134Glu + Asn140Ser + Phe193Ile Ala164Gln + Ala168Glu + Trp208Asn + Tyr210Leu Val103Pro + Gly139Pro + Asn163Asp + Gly165Gln Gly162Ser + Trp208Glu + Tyr210Ser + Leu221Gln Serl41Asp + Tyr171His + Trp208Ala + Leu221Met Asn 66Ser + Gly139Gln + Asn163Gln + Tyr210Thr Leu134Asp + Gly136Ser + Asn163Gln + Trp208Val Ser191Asp + Phe193Leu + Pro214Gln + Thr217Ser Gly 67Asn + Gly108Asp + Thr195Asn + Thr215Pro Ala114Thr + Asn140GIu + Asn166Ser + Ala203Pro Ser191Glu + Ala203Gly + Trp208Asn + Tyr210Ala Asn140Asp + Ser141Glu + Ala164Gln + Tyr218Ser Thr 73Ser + Tyr213Val + Ser220Glu + Leu221Glu Phe193Met + Thr215Gln + Ser220Glu + Leu221Glu Thr113Ser + Trp208Leu + Ser220Glu + Leu221Glu Thr 73Pro + Val115Ala + Ser192Asp + Phe193Glu Ala114Asn + Trp208Pro + Tyr210Glu + Ser220Glu Trp208Cys + Tyr210Glu + Ala219Asn + Ser220Asp Ala114Pro + Gly139Pro + Tyr210Asp + Ser220Glu Tyr210Glu + Thr217Gln + Tyr218Gln + Ser220Glu Asn140Ser + Trp208Glu + Ser220Asp + Leu221Asp Val103Pro + Trp208Glu + Tyr210Ser + Ser220Glu Thr 73Gln + Ser107Asp + Ser109Glu + Asn163Gln Gly 67Gln + Ser107Asp + Ser109Glu + Leu221Cys Asp105Glu + Asn106Ser + Ser109Glu + Thr217Pro Leu104Glu + Asp105Glu + Ser107Asp + Leu221Ser Gly206Pro + Pro214Asp + Thr217Glu + Leu221Asn Ser207Asp + Trp208Glu + Ser220Asp + Leu221Ser Gly135Asp + Gly162Glu + Tyr171Asp + Thr217Ser Gly 69Glu + Leu104Asp + Asp105Glu + Tyr210Ala Ala168Asn + Ser220Asp + Leu221Pro + Ser222Asp Phe193Gln + Ser207Glu + Thr217Ser + Leu221Glu Gly110Gln + Gly165Gln + Ser222Asp + Thr224Asp Asn106Glu + Ser109Asp + Phe193Ile + Trp208Leu Gly110Asn + Thr137Glu + Pro169Asp + Asn170Ser Gly136Glu + Gly162Glu + Trp208Ala + Thr217Asn Leu134Ile + Ser191Glu + Leu221His + Gly223Glu Gly139Pro + Tyr171Met + Ser207Asp + Ser220Glu Val103Pro + Thr111Gly + Ser207Asp + Ser220Asp Gly108Asn + Thr195Gly + Ser207Asp + Ser220Asp Ser 70Glu + Val103Pro + Asn106Asp + Ala168Pro Thr113Gly + Gly162Ser + Asn163Asp + Asn170Glu Leu104Ile + Ser107Glu + Gly110Asp + Asn170Gln Thr 73Gly + Gly135Asp + Pro169Asp + Trp208Thr Tyr210Met + Thr215Asp + Tyr218Glu + Leu221Asn Leu104Thr + Gly136Glu + Pro169Asp + Leu221Val Asn 66Asp + Thr 73Glu + Tyr218Ile + Leu221Cys Asp105Glu + Thr111Asp + Ala114Pro + Val138Met Asn 68Glu + Thr 73Glu + Trp208Tyr + Thr217Asn Ser207Glu + Tyr213Ile + Ala219Asp + Ser222Asp Asn163Asp + Ala164Ser + Ser191Asp + Ser207Glu Thr 73Glu + Ala168Ser + Tyr210Glu + Tyr218Glu Gly 67Glu + Trp208Ile + Pro214Asn + Thr215Asp Asp105Glu + Thr111Glu + Thr113Glu + Asn163Gln Ser 70Glu + Tyr210His + Thr217Asp + Leu221Ala Gly 67Glu + Gly108Asp + Thr137Gln + Thr167Pro Ser107Asp + Gly110Asp + Ala114Glu + Tyr218Asn Ser 70Asp + Tyr210Glu + Thr217Asn + Ser220Glu Thr113Gly + Trp208Glu + Ser220Asp + Thr224Asp Val138Met + Ala219Glu + Ser222Asp + Thr224Gln Ser 70Glu + Trp112Tyr + Tyr218Cys + Leu221Glu Gly 67Ser + Ser 70Glu + Pro169Asn + Leu221Asp Val115Cys + Gly139Asn + Thr217Asp + Ser220Asp Gly 69Ser + Val115Thr + Thr217Glu + Ser220Glu Ala168His + Trp208Tyr + Thr217Asp + Ser220Glu Thr111Gln + Gly135Pro + Thr217Asp + Ser220Glu Ala164Thr + Ser191Glu + Trp208Glu + Thr215Asn Asn 68Glu + Val103Glu + Ser109Glu + Asn166Gln Ser 70Asp + Gly139Ser + Thr217Glu + Ser220Asp Leu134Asp + Phe193Glu + Ala203Ser + Gly223Asp Asn 66Asp + Asn 68Ser + Ser216Asp + Thr217Glu Ala164Glu + Trp208Cys + Leu221Glu + Ser222Asp Ser 70Glu + Ser207Glu + Ala219Ser + Ser220Glu Gly 67Asp + Ser 70Asp + Thr 73Gly + Tyr210Glu Trp208Ile + Thr217Glu + Tyr218Asp + Ser222Asp Leu104Ile + Thr111Glu + Gly135Asp + Asn163Gln Ala114Glu + Leu134Ile + Ala219Glu + Ser220Asp Asn166Glu + Thr167Gly + Ser222Asp + Gly223Asp Gly139Glu + Tyr210Ala + Ser222Asp + Gly223Glu Val103Gly + Gly110Glu + Thr111Glu + Ser222Glu Ala114Glu + Asn170Ser + Ser216Asp + Thr217Glu Gly108Asp + Ser109Asp + Tyr210Gln + Thr217Glu Asn 68Ser + Ser109Asp + Gly110Glu + Ser220Glu Asn 68Glu + Asn163Ser + Ser207Asp + Trp208Glu Ser207Asp + Trp208Glu + Thr217Glu + Leu221Cys Gly 69Pro + Asp105Glu + Asn106Asp + Asn166Asp Ser109Asp + Tyr210Gln + Ser220Glu + Leu221Asp Tyr171Gly + Ser192Glu + Ser220Asp + Leu221Glu Asn170Glu + Ser191Glu + Ser192Glu + Pro205Ser Asn 66Asp + Tyr210Gln + Thr217Glu + Tyr218Glu Asn106Asp + Ser107Glu + Thr137Asp + Tyr210Gln Ser192Asp + Phe193Glu + Pro205Ser + Thr217Asp Ser 70Asp + Gly162Asp + Asn163Glu + Leu221Ser Gly 69Asn + Asn106Glu + Tyr210Asp + Ser220Glu Val103Ser + Asn140Asp + Tyr210Glu + Ser220Asp Gly 69Glu + Phe193His + Ser207Glu + Ser222Asp Gly162Glu + Asn163Gln + Trp208Asp + Ser220Glu Val115Cys + Asn170Asp + Trp208Asp + Ser220Asp Gly110Glu + Trp208Asp + Leu221Asn + Ser222Glu Pro169Asp + Tyr171Glu + Pro214Asn + Gly223Glu Asn163Glu + Ser207Glu + Trp208Met + Tyr210Thr Gly 67Glu + Ser 70Glu + Val115Cys + Gly162Glu Gly162Glu + Ala164Glu + Ser220Glu + Leu221Gly Asn 66Glu + Val103Asp + Gly108Asn + Leu221Met Asp105Glu + Ser109Glu + Tyr218Asp + Leu221Ala Gly 67Asp + Ala164Asp + Ala168Glu + Tyr213Asn Gly 69Pro + Ser141Asp + Pro214Asp + Thr217Asp Thr 73Glu + Trp112Ile + Trp208Gly + Ser220Asp Gly 72Ser + Ser107Asp + Thr111Asp + Asn166Gln Gly165Glu + Ser192Asp + Thr217Asp + Leu221Ile Gly135Glu + Asn140Glu + Ala204His + Pro214Ser Asp105Glu + Gly110Asp + Asn170Asp + Ala219Gly Asn 66Asp + Asn 68Asp + Leu134Gly + Asn163Glu Leu104Thr + Ala168Asp + Asn170Asp + Ser220Glu Thr 73Asp + Ser109Glu + Pro214Glu + Thr217Asn Thr 73Asp + Val115Cys + Pro214Asp + Thr224Glu Ser109Asp + Thr113Asp + Leu134Asn + Phe193Pro Gly 69Ser + Gly108Asp + Gly110Asp + Ser220Glu Gly139Asp + Ser141Asp + Ala164Asp + Leu221Val Asn 66Asp + Trp208Met + Ser220Asp + Ser222Glu Trp112Asp + Tyr210Thr + Ser220Glu + Ser222Glu Ser109Asp + Ser207Glu + Tyr210Gly + Leu221Glu Gly 69Asp + Asp105Glu + Thr137Asp + Trp208Asn Ser109Asp + Thr111Glu + Ser191Glu + Tyr210Leu Gly139Gln + Pro169Asp + Ser191Asp + Ser207Glu Gly 67Ser + Asn140Asp + Ser222Asp + Thr224Glu Val138Asp + Asn170Glu + Trp208His + Thr215Glu Asn 68Asp + Thr111Gly + Val138Asp + Asn170Asp Leu104Glu + Ser107Asp + Gly135Gln + Tyr171Asp Leu104Pro + Trp112Asp + Asn140Glu + Ser222Glu Gly139Glu + Asn170Asp + Gly206Pro + Ser220Glu Ala164Asp + Asn170Asp + Ser216Asp + Thr217Pro Thr113Glu + Ala114His + Ser207Glu + Ser220Glu Gly110Glu + Val115Gln + Ser207Asp + Thr224Glu Asn106Glu + Asn163Glu + Asn170Glu + Leu221His Gly 69Asp + Thr 73Glu + Thr113Asn + Ser141Glu Gly 69Asp + Thr 73Asp + Thr111Gly + Gly139Glu Ser107Asp + Asn163Glu + Ser192Asp + Trp208Met Asn 68Asp + Gly108Asp + Ser207Asp + Ile209Ala Gly135Asp + Gly139Pro + Pro169Asp + Trp208Glu Asn 66Glu + Thr167Gly + Trp208Glu + Pro214Asp Asn 66Asp + Ser109Asp + Trp208Gly + Pro214Glu Gly 69Glu + Asn140Ser + Ser192Glu + Pro214Asp Leu104Gly + Gly139Glu + Ser191Asp + Thr224Asp Asn106Gln + Thr113Asp + Asn163Asp + Asn166Glu Leu134Glu + Ser207Asp + Trp208Pro + Tyr210Glu Ser191Glu + Thr195Asn + Tyr218Pro + Leu221Glu Asn170Asp + Phe193Ser + Ser220Glu + Thr224Asp Asp105Glu + Ala114Glu + Ser192Glu + Thr224Asn Gly 67Asp + Gly108Asp + Ser207Asp + Tyr210Cys Asn 68Asp + Gly110Glu + Thr113Gly + Leu221Ala Leu104Ile + Ala114Glu + Ser220Glu + Gly223Glu Ser107Asp + Ser220Glu + Leu221Pro + Gly223Asp Va1103Asp + Val138Glu + Ser141Glu + Gly206Gln Val138Glu + Ser141Asp + Tyr210Gln + Ser220Asp Asn 68Asp + Val115Gly + Thr217Asp + Ser220Glu Asn 66Asp + Leu104Gly + Ala168Thr + Ser216Glu Val103Glu + Asn106Glu + Thr113Pro + Ser220Asp Asp105Glu + Thr113Asp + Gly139Asn + Ser141Glu Ser 70Glu + Asp105Glu + Gly139Asp + Tyr210Ala Asn 66Glu + Tyr210Asp + Thr217Glu + Leu221Ala Gly108Glu + Gly135Ser + Tyr210Asp + Thr217Glu Gly 69Asp + Gly108Gln + Trp112Asp + Ser141Glu Ser107Glu + Gly110Pro + Thr217Asp + Ser220Asp Gly135Glu + Thr217Glu + Tyr218Val + Ser220Glu Asn163Asp + Tyr171Thr + Thr217Asp + Ser220Asp Ala114Thr + Thr137Glu + Thr217Asp + Ser220Asp Asn166Glu + Thr212Pro + Thr217Asp + Ser220Asp Gly 67Asp + Ser107Asp + Tyr210Asn + Ser222Glu Asn140Ser + Trp208Gly + Thr217Glu + Leu221Asp Asn166Gln + Thr215Pro + Thr217Glu + Leu221Asp Val115Gln + Ala168Gln + Phe193Asp + Leu221Asp Trp208Ile + Pro214Ser + Ser220Glu + Thr224Glu Gly108Glu + Thr137Glu + Asn163Asp + Trp208Ser Gly139Pro + Ala164Glu + Ser191Asp + Pro214Glu Thr 73Asp + Thr111Pro + Asn166Asp + Ser191Asp Ser 70Glu + Ala168His + Thr195Glu + Ser216Asp Ser109Glu + Thr137Asp + Gly139Ser + Ala164Gln Asn170Gln + Tyr210Asp + Pro214Glu + Gly223Ser Ser 70Glu + Gly139Asn + Ala164Glu + Ser220Asp Asn 66Asp + Thr113Glu + Ser141Asp + Trp208Gly Asn 66Asp + Gly108Glu + Thr215Gly + Leu221Ser Asn 68Ser + Thr 73Glu + Asn166Glu + Leu221Asp Thr 73Asp + Ser192Asp + Ser220Asp + Leu221Met Ser107Asp + Thr111Asp + Ser192Glu + Thr217Ser ...
Table 35
Many ring five sudden change varient Asn 66Gln+Gly 67Ser+Leu104Gly+Tyr210Pro+
Thr217GluGly?69Ser?+?Val103Gln?+?Trp112Cys?+?Thr217Gly?+
Gly223AspVal115Pro?+?Leu134Ile?+?Ala164Glu?+?Phe193Asn?+
Trp208GlnLeu104Gly?+?Thr113Ser?+?Ala168Glu?+?Asn170Ser?+
Ala219GlyGly?69Ser?+?Ser109Asp?+?Thr111Gln?+?Val115Ala?+
Tyr210ProVal103Thr?+?Gly108Glu?+?Val115Pro?+?Tyr171Ser?+
Trp208AsnLeu134Ala?+?Val138Cys?+?Asn163Gln?+?Tyr171Ser?+
Ser220AspAsn?66Ser?+?Val115Gly?+?Ser191Glu?+?Trp208Ile?+
Thr217SerGly?72Asn?+?Trp112Phe?+?Val115Ala?+?Asn166Gln?+
Trp208GlyLeu134His?+?Gly165Gln?+?Trp208Pro?+?Tyr210Val?+
Thr217GluLeu104Pro?+?Tyr171Leu?+?Trp208Leu?+?Ala219Glu?+
Leu221SerAsn166Glu?+?Thr167Pro?+?Tyr210Pro?+?Tyr213Ile?+
Pro214AsnGly139Gln?+?Asn170Glu?+?Trp208Cys?+?Thr215Ser?+
Leu221AsnAla114Glu?+?Gly135Ser?+?Ala168Thr?+?Ala203Thr?+
Trp208MetAla164His?+?Ala168His?+?Phe193Ala?+?Thr217Ser?+
Ser220AspGly?67Pro?+?Gly?69Ser?+?Ser191Asp?+?Tyr218Val?+
Thr224SerGly139Asn?+?Ala164Pro?+?Phe193Pro?+?Thr217Asn?+
Leu221CysLeu104Met?+?Ser207Asp?+?Trp208Ala?+?Thr212Gly?+
Thr217ProLeu134Val?+?Trp208Thr?+?Pro214Gly?+?Leu221Ile?+
Thr224AspSerl09Asp?+?Ala114Asn?+?Val115Asn?+?Gly165Gln?+
Tyr210SerLeu104Ser?+?Gly110Pro?+?Gly136Glu?+?Ala168Thr?+
Ala219GlnGly110Pro?+?Leu134Pro?+?Asn166Asp?+?Asn170Ser?+
Trp208AsnThr113Gln?+?Pro169Gly?+?Asn170Gln?+?Tyr218Gln?+
Leu221SerThr137Ser?+?Thr195Gln?+?Ser207Glu?+?Trp208Gln?+
Thr217ProGly?69Gln?+?Val103Gly?+?Trp112Met?+?Trp208Asn?+
Pro214GlyGly136Pro?+?Gly162Ser?+?Trp208Ile?+?Tyr210Gly?+
Pro214GlnThr137Asp?+?Gly165Gln?+?Thr195Ser?+?Trp208Pro?+
Thr212SerAsn?66Ser?+?Pro169Ser?+?Tyr210Asn?+?Tyr218Asn?+
Gly223GluSer?70Glu?+?Asn106Gln?+?Val138Ala?+?Ala168Gln?+
Leu221ValGly?69Ser?+?Thr113Asp?+?Ala114Gln?+?Trp208Thr?+
Ala219SerThr113Gln?+?Ala168Asp?+?Pro169Ser?+?Asn170Ser?+
Ala219ThrGly139Ser?+?Asn170Gln?+?Tyr171Leu?+?Trp208Cys?+
Thr215SerGly?67Ser?+?Ala114Asn?+?Gly139Ser?+?Tyr210Thr?+
Tyr218SerTrp112Glu?+?Ala164Pro?+?Tyr171Pro?+?Thr195Asn?+
Thr217SerGly?67Glu?+?Val115Asn?+?Gly162Gln?+?Gly165Gln?+
Phe193ValGly135Ser?+?Tyr171Cys?+?Trp208His?+?Tyr210Met?+
Leu221ValGly?69Asn?+?Asn106Ser?+?Asn166Glu?+?Tyr210Cys?+
Leu221GlyGly135Ser?+?Tyr171Asn?+?Trp208His?+?Ser216Glu?+
Leu221GlyGly?69Asn?+?Ser109Asp?+?Gly165Asn?+?Phe193Asn?+
Trp208HisPro169Ser?+?Ser207Glu?+?Pro214Asn?+?Thr215Asn?+
Thr217GlySer?70Asp?+?Asn163Ser?+?Tyr210Val?+?Tyr213Asn?+
Leu221AlaGly108Gln?+?Gly110Ser?+?Gly135Gln?+?Thr137Asn?+
Trp208GluAsn?68Ser?+?Ala164Gln?+?Asn170Glu?+?Thr217Ser?+
Gly223SerGly?69Ser?+?Trp112Cys?+?Ala164Gly?+?Leu221Ser?+
Gly223GluGly?69Glu?+?Gly?72Gln?+?Thr137Pro?+?Trp208Ile?+
Tyr218ProVal103Gln?+?Val138His?+?Gly162Ser?+?Asn166Asp?+
Trp208HisVal115Gln?+?Leu134Cys?+?Ala168Ser?+?Pro169Asp?+
Tyr210SerGly?67Gln?+?Trp112Leu?+?Phe193His?+?Thr195Glu?+
Thr217SerGly?67Gln?+?Leu104Asn?+?Ala164Glu?+?Ala204Ser?+
Pro205SerGly135Ser?+?Val138Ser?+?Asn140Glu?+?Tyr210Leu?+
Thr217GlyGly?67Asn?+?Thr?73Ser?+?Tyr171Leu?+?Phe193Tyr?+
Tyr210ProGly135Pro?+?Trp208His?+?Tyr210Leu?+?Ala219Ser?+
Leu221GlnAsn?68Gln?+?Asn106Glu?+?Thr137Gln?+?Pro169Gln?+
Thr215GlnThr137Asp?+?Val138Gln?+?Trp208Ile?+?Tyr218Leu?+
Leu221CysGly?67Asn?+?Gly165Asn?+?Phe193Tyr?+?Pro205Ser?+
Trp208CysAsn?66Ser?+?Thr?73Ser?+?Ser107Asp?+?Ala168Ser?+
Tyr210CysThr137Gly?+?Tyr210Pro?+?Thr215Pro?+?Ser216Asp?+
Thr217SerThr?73Pro?+?Trp112Asp?+?Gly139Pro?+?Thr215Pro?+
Leu221HisLeu104Cys?+?Thr111Pro?+?Trp208Pro?+?Leu221Cys?+
Ser222AspThr113Gln?+?Ala204His?+?Trp208Phe?+?Thr217Asp?+
Leu221CysThr111Gly?+?Gly139Gln?+?Tyr171Leu?+?Tyr210Met?+
Thr217GluGly110Asn?+?Val115Gln?+?Pro169Gln?+?Thr195Gly?+
Ser220AspTyr171Asp?+?Gly206Ser?+?Thr217Gln?+?Ala219Gly?+
Leu221ThrSer109Glu?+?Thr111Ser?+?Val115Cys?+?Val138Cys?+
Tyr171SerLeu104His?+?Asn163Asp?+?Trp208Thr?+?Tyr210Cys?+
Thr217AsnGly136Asn?+?Gly139Pro?+?Ser141Glu?+?Pro169Gln?+
Ala219HisGly?69Ser?+?Gly136Ser?+?Thr137Asn?+?Thr195Pro?+
Ala219GluAsn106Asp?+?Gly162Ser?+?Asn163Gln?+?Pro169Gly?+
Leu221ProAla168Gly?+?Phe193Met?+?Pro205Asn?+?Tyr210Asn?+
Leu221AsnGly?69Pro?+?Gly139Asp?+?Ala164Gly?+?Tyr213Ser?+
Thr217SerGly?72Ser?+?Leu104Gln?+?Asn166Glu?+?Pro169Asn?+
Thr215GlyLeu134Cys?+?Trp208Asn?+?Tyr210Ala?+?Tyr218Gly?+
Thr224GlyLeu104Gln?+?Thr195Asn?+?Trp208Val?+?Tyr210Pro?+
Leu221CysGly?67Pro?+?Thr?73Asn?+?Trp208Pro?+?Ala219Asn?+
Ser220AspThr?73Gln?+?Gly108Pro?+?Gly139Pro?+?Ser192Glu?+
Gly223GlnAsn?68Glu?+?Thr?73Gln?+?Pro169Gln?+?Tyr210Pro?+
Leu221MetLeu104His?+?Thr113Gln?+?Asn140Gln?+?Thr167Asn?+
Phe193AspGly?67Pro?+?Asn?68Ser?+?Gly139Asp?+?Thr215Gly?+
Thr217ProGly136Ser?+?Val138Met?+?Thr167Gln?+?Tyr218Asn?+
Ser220AspAsp105Glu?+?Gly110Ser?+?Trp112His?+?Tyr210Gln?+
Ala219ThrAsn?68Asp?+?Asn106Gln?+?Ala164Ser?+?Thr195Gln?+
Trp208CysLeu104Val?+?Leu134Ala?+?Thr137Asn?+?Asn170Asp?+
Leu221IleGly?67Ser?+?Leu134Met?+?Trp208Ala?+?Tyr210Ser?+
Thr217ProAla114Gly?+?Gly135Asp?+?Gly139Ser?+?Asn170Ser?+
Thr217SerThr111Asn?+?Phe193Ser?+?Pro205Gln?+?Trp208Thr?+
Leu221GluSer109Asp?+?Val138Asn?+?Phe193Ala?+?Trp208Cys?+
Thr212GlnSer?70Asp?+?Asn166Ser?+?Ile209Pro?+?Tyr210Met?+
Leu221SerAsn106Ser?+?Leu134Cys?+?Gly136Ser?+?Ala168Thr?+
Tyr210GluGly?67Gln?+?Leu134Gln?+?Gly135Asp?+?Phe193His?+
Thr224GlyAsn?68Ser?+?Leu104Ala?+?Gly162Asp?+?Tyr171Met?+
Thr217GlyAsn163Glu?+?Thr212Gln?+?Thr215Asn?+?Thr217Asn?+
Leu221MetGly?69Gln?+?Asn106Gln?+?Ser207Glu?+?Trp208Thr?+
Thr217GlyGly139Glu?+?Ala168His?+?Thr195Gly?+?Leu221His?+
Thr224AsnGly?72Ser?+?Ala114Asn?+?Leu134His?+?Pro169Glu?+
Trp208TyrVal138Ser?+?Ala164Asn?+?Tyr210Cys?+?Tyr218Leu?+
Ser220AspLeu104Gln?+?Tyr171Glu?+?Trp208Gly?+?Thr217Gln?+
Ala219HisAsn106Ser?+?Tyr171Gly?+?Phe193Gln?+?Thr215Gln?+
Ala219GlnGly?72Ser?+?Gly108Asn?+?Trp112Ile?+?Asn166Glu?+
Leu221CysAsn?68Ser?+?Leu104Thr?+?Thr215Ser?+?Ala219Thr?+
Thr224AspVal138Ser?+?Asn163Asp?+?Phe193Cys?+?Pro205Asn?+
Thr217SerGly?67Ser?+?Tyr210Pro?+?Tyr218Thr?+?Ser220Asp?+
Leu221SerGly135Asn?+?Gly136Gln?+?Gly162Ser?+?Tyr210Asn?+
Pro214AsnThr195Ser?+?Trp208Pro?+?Tyr210Gly?+?Ala219Ser?+
Leu221IleAsn?68Glu?+?Thr111Pro?+?Asn163Ser?+?Phe193Tyr?+
Leu221ValGly?67Ser?+?Thr?73Pro?+?Asn170Glu?+?Tyr210Leu?+
Leu221ValGly135Asn?+?Gly139Ser?+?Phe193Asp?+?Thr217Gly?+
Leu221GlyGly136Gln?+?Gly139Gln?+?Gly165Ser?+?Tyr210Asp?+
Thr217ProSer141Glu?+?Gly162Pro?+?Thr167Gly?+?Tyr210Ile?+
Thr217SerLeu104Pro?+?Gly110Pro?+?Gly136Pro?+?Pro205Asn?+
Thr217GluVal115Ala?+?Ala164Thr?+?Ser192Asp?+?Trp208Leu?+
Tyr210MetThr?73Asn?+?Val103Asn?+?Thr215Asn?+?Thr217Gln?+
Ser222AspVal103Pro?+?Trp208Tyr?+?Ile209Cys?+?Tyr210Thr?+
Thr217GlnTrp112Phe?+?Ala114Ser?+?Pro169Gln?+?Ser220Glu?+
Leu221HisGly108Asn?+?Leu134Met?+?Tyr210Ser?+?Tyr213Ile?+
Pro214GluAla168Pro?+?Trp208His?+?Tyr210Ala?+?Ser220Glu?+
Leu221GlnGly139Pro?+?Asn140Glu?+?Ser141Asp?+?Asn166Ser?+
Trp208ThrVal103Asn?+?Thr111Gly?+?Tyr210Gln?+?Ser216Asp?+
Thr217GluVal138His?+?Gly139Asn?+?Ser207Asp?+?Trp208Glu?+
Leu221GlnAla168Asn?+?Pro169Gly?+?Thr217Pro?+?Ser220Asp?+
Leu221AspTyr210Leu?+?Ala219Gly?+?Ser220Asp?+?Leu221Asp?+
Gly223SerVal103Ala?+?Pro169Asn?+?Thr217Gln?+?Ser220Asp?+
Leu221AspThr?73Asn?+?Asn170Asp?+?Tyr171Glu?+?Tyr210Ile?+
Leu221SerGly136Ser?+?Ser191Asp?+?Ser192Glu?+?Tyr218Cys?+
Leu221AsnThr?73Pro?+?Val115Ala?+?Ser192Asp?+?Phe193Glu?+
Trp208GlnThr137Gln?+?Gly162Asp?+?Asn163Asp?+?Ala203His?+
Pro205GlnAsn163Gln?+?Tyr210Asp?+?Thr215Pro?+?Ser220Glu?+
Gly223ProAsp105Glu?+?Asn106Glu?+?Ser107Asp?+?Trp208Phe?+
Tyr210SerTrp112Gly?+?Phe193Gln?+?Ser207Asp?+?Trp208His?+
Ser222AspGly108Asn?+?Ser207Glu?+?Tyr213Thr?+?Thr215Pro?+
Ser222AspLeu134Met?+?Ser207Asp?+?Trp208Val?+?Tyr210His?+
Ser222AspGly?69Glu?+?Asn106Asp?+?Ala114His?+?Ala168Ser?+
Thr217GlnLeu104Pro?+?Trp208Glu?+?Thr212Asn?+?Thr215Ser?+
Ser222AspThr111Pro?+?Thr137Asn?+?Pro169Gln?+?Tyr210Glu?+
Ala219GluThr?73Gly?+?Val115Gly?+?Trp208Glu?+?Tyr210Asp?+
Ser220GluGly135Gln?+?Gly136Glu?+?Asn170Ser?+?Tyr171Glu?+
Trp208GlnThr?73Ser?+?Ser107Asp?+?Ser109Asp?+?Gly136Pro?+
Tyr210GlyLeu134Pro?+?Pro169Gln?+?Pro214Glu?+?Ser216Glu?+
Thr217GlyAsp105Glu?+?Ser109Glu?+?Pro169Gly?+?Tyr171Gln?+
Thr212SerGly135Pro?+?Val138Ala?+?Ser207Asp?+?Tyr210Thr?+
Gly223GluGly135Pro?+?Ser207Glu?+?Trp208Ala?+?Tyr210Pro?+
Gly223GluPro169Gln?+?Phe193Val?+?Tyr210Glu?+?Thr215Asn?+
Leu221AspAla114Gln?+?Gly136Ser?+?Ala219Asn?+?Ser220Asp?+
Ser222AspLeu134Ser?+?Thr167Gly?+?Ser220Asp?+?Leu221Pro?+
Ser222AspGly108Gln?+?Trp112Leu?+?Tyr218Glu?+?Ser220Asp?+
Leu221GluGly108Pro?+?Ala114Asn?+?Ser207Asp?+?Tyr210Glu?+
Ser220GluThr137Glu?+?Gly162Glu?+?Pro169Asn?+?Asn170Ser?+
Tyr171AspAsn?68Gln?+?Gly162Glu?+?Ala164Thr?+?Gly165Asp?+
Tyr171AlaThr137Pro?+?Gly139Asp?+?Asn170Glu?+?Trp208Met?+
Tyr210ThrAsn?68Gln?+?Val138Ser?+?Gly162Pro?+?Ala164Glu?+
Asn170AspAsn?68Gln?+?Ser207Glu?+?Trp208Thr?+?Thr217Ser?+
Ser220AspVal138Ala?+?Phe193Thr?+?Ser207Asp?+?Tyr210Met?+
Ser220AspPhe193Ala?+?Trp208Glu?+?Ile209Ser?+?Leu221Cys?+
Gly223GluThr111Gly?+?Phe193Gln?+?Ser207Asp?+?Ser220Asp?+
Gly223GluSer?70Asp?+?Asp105Glu?+?Gly108Glu?+?Thr111Ser?+
Tyr210ValGly136Glu?+?Gly162Asp?+?Gly165Ser?+?Ala168Pro?+
Thr195GluLeu104Gly?+?Gly165Glu?+?Pro169Glu?+?Thr217Asn?+
Leu221AlaThr195Asn?+?Tyr210Asp?+?Thr217Glu?+?Ser220Glu?+
Gly223ProTrp208Phe?+?Tyr210Asp?+?Tyr213Cys?+?Thr217Glu?+
Ser220GluSer?70Asp?+?Gly108Glu?+?Tyr171Gly?+?Thr217Gln?+
Leu221ProThr195Gly?+?Ser207Glu?+?Tyr210Glu?+?Tyr213Cys?+
Ala219SerAsn?68Glu?+?Asp105Glu?+?Gly110Asp?+?Thr111Pro?+
Asn140SerSer?70Asp?+?Val103Gln?+?Pro214Gln?+?Ser220Asp?+
Leu221GluAsn?66Asp?+?Thr?73Glu?+?Asn106Ser?+?Trp208His?+
Leu221ThrAla164Asp?+?Thr167Asp?+?Tyr171Pro?+?Ala219Gln?+
Leu221ThrAla114His?+?Ala219Gly?+?Ser220Glu?+?Ser222Glu?+
Thr224GluAsn106Asp?+?Ser109Asp?+?Thr111Asp?+?Thr137Ser?+
Pro205AsnLeu104Cys?+?Asn163Glu?+?Ser192Asp?+?Ala219Pro?+
Ser222GluGly162Asp?+?Ala164Gln?+?Ser207Asp?+?Trp208Tyr?+
Gly223AspSer?70Asp?+?Ser107Glu?+?Ser109Glu?+?Val115Cys?+
Gly135SerAla114Gly?+?Ala219Asp?+?Ser220Glu?+?Leu221Asn?+
Gly223GluAsn?66Asp?+?Asp105Glu?+?Val115Gln?+?Thr137Ser?+
Trp208HisGly?69Glu?+?Thr?73Glu?+?Val103His?+?Ser107Asp?+
Leu221AlaGly108Pro?+?Trp112Gln?+?Gly162Asn?+?Ser220Glu?+
Gly223AspAsn?68Asp?+?Asn170Gln?+?Tyr171Pro?+?Thr215Asp?+
Ser216AspSer?70Asp?+?Tyr171Ser?+?Thr195Gly?+?Tyr210Asp?+
Ser220GluThr113Gly?+?Gly162Ser?+?Trp208Glu?+?Ser220Asp?+
Thr224AspSer?70Glu?+?Asn140Ser?+?Ala203Gln?+?Ala219Glu?+
Gly223ProTrp112Pro?+?Asn170Ser?+?Ser216Asp?+?Thr217Asp?+
Ser220AspThr?73Asn?+?Val138Asp?+?Pro169Glu?+?Asn170Ser?+
Thr217GlySer?70Asp?+?Asp105Glu?+?Gly162Pro?+?Trp208Val?+
Thr217SerGly?67Asn?+?Asn140Ser?+?Ala219Glu?+?Leu221Met?+
Ser222GluGly?72Ser?+?Gly110Pro?+?Trp112Ala?+?Tyr210Asp?+
Thr217GluGly108Pro?+?Trp112Leu?+?Leu134Cys?+?Gly135Asp?+
Ala164AspAsn?66Gln?+?Trp208Ala?+?Thr217Glu?+?Ser220Glu?+
Leu221ThrThr?73Gly?+?Leu134Ser?+?Thr217Glu?+?Ser220Glu?+
Leu221AsnGly?67Ser?+?Ala168Gly?+?Pro214Gln?+?Thr217Glu?+
Ser220AspVal115Cys?+?Glyl39Asn?+?Tyr210Cys?+?Thr217Asp?+
Ser220AspLeu134Glu?+?Thr137Glu?+?Thr195Asn?+?Trp208Ser?+
Leu221SerAla164Gln?+?Tyr210Val?+?Thr215Asp?+?Thr217Glu?+
Ser220AspGly?67Asp?+?Ser?70Asp?+?Thr217Gly?+?Tyr218Asp?+
Leu221IleSer?70Asp?+?Thr111Asn?+?Trp208Cys?+?Thr217Glu?+
Ser220GluLeu134Glu?+?Gly162Ser?+?Asn166Gln?+?Ser207Asp?+
Gly223AspGly162Pro?+?Thr167Asn?+?Pro169Glu?+?Ser191Glu?+
Phe193AspSer?70Glu?+?Trp112Tyr?+?Ser207Glu?+?Tyr218Cys?+
Leu221GluAsn?66Glu?+?Leu104Glu?+?Ser107Asp?+?Trp208Ser?+
Thr215ProLeu104Ala?+?Gly135Asp?+?Thr195Asp?+?Tyr213Ile?+
Thr217GlyThr167Gln?+?Ser192Glu?+?Ser207Glu?+?Trp208Cys?+
Ser220AspGly165Pro?+?Ser191Asp?+?Trp208Gly?+?Ser220Asp?+
Leu221GluGly135Glu?+?Asn163Asp?+?Tyr213Met?+?Leu221His?+
Ser222AspThr111Asp?+?Gly136Glu?+?Gly162Glu?+?Ala164Asn?+
Pro214SerThr113Gln?+?Tyr213Thr?+?Ser216Glu?+?Thr217Glu?+
Leu221GluSer?70Glu?+?Glyl08Glu?+?Ala164Gly?+?Gly165Gln?+
Leu221AspSer?70Glu?+?Leu104Gln?+?Ser220Asp?+?Leu221His?+
Gly223ProGly165Asp?+?Pro169Ser?+?Ser207Glu?+?Trp208Gly?+
Ser222AspAla168Pro?+?Pro169Asn?+?Thr215Asp?+?Thr217Asp?+
Leu221GluGly110Pro?+?Thr113Ser?+?Gly165Glu?+?Trp208Asp?+
Ser222AspGly110Glu?+?Thr113Asp?+?Gly139Glu?+?Trp208Tyr?+
Tyr210AlaAsn?68Glu?+?Asn106Glu?+?Tyr171His?+?Tyr210Gln?+
Ser216GluAla164Glu?+?Ala168His?+?Ala219Glu?+?Ser220Asp?+
Leu221CysAsn?68Asp?+?Tyr210Gln?+?Ala219Glu?+?Ser220Glu?+
Leu221SerThr?73Asp?+?Asn163Ser?+?Ala219His?+?Ser222Glu?+
Gly223GluGly?67Asp?+Asn?68Glu?+?Ala168Gln?+?Pro169Glu?+
Phe193AsnGly110Asp?+?Gly139Gln?+?Asn140Glu?+?Ser141Glu?+
Tyr218AsnSer109Glu?+?Ser216Glu?+?Thr217Asp?+?Tyr218Asn?+
Leu221HisGly135Pro?+?Gly136Ser?+?Phe193Asp?+?Ser216Asp?+
Thr217GluGly165Gln?+?Ser192Glu?+?Ala203Ser?+?Ser216Asp?+
Thr217AspGly?67Gln?+?Leu134His?+?Gly136Asp?+?Ser207Asp?+
Trp208GluVal103Ser?+?Ser207Asp?+?Trp208Glu?+?Thr217Glu?+
Leu221CysGly?69Pro?+?Asp105Glu?+?Asn106Asp?+?Asn166Asp?+
Ile209ThrTrp112Tyr?+?Asn170Glu?+?Trp208Gln?+?Ser220Glu?+
Leu221GluThr137Gly?+?Gly139Gln?+?Gly162Asp?+?Ser220Glu?+
Leu221AspThr113Asp?+?Ala164Gly?+?Ser191Glu?+?Ser192Glu?+
Thr195GlySer107Glu?+?Thr113Glu?+?Ala114Asp?+?Tyr210Pro?+
Leu221AlaAsn?66Asp?+?Gly?67Asp?+?Leu134Pro?+?Tyr210Asn?+
Ser222AspAsn?68Gln?+?Leu104Ala?+?Pro169Asp?+?Asn170Glu?+
Leu221AspAsn106Glu?+?Ser107Asp?+?Gly139Asp?+?Ala203Asn?+
Thr217SerThr?73Gly?+?Thr137Glu?+?Tyr210Asp?+?Thr217Gln?+
Ser220GluTrp112Ile?+?Gly136Glu?+?Phe193Thr?+?Tyr210Glu?+
Ser220GluTrp112Ala?+?Asn163Ser?+?Ser192Glu?+?Tyr210Glu?+
Ser220GluSer?70Glu?+?Thr?73Ser?+?Val103Asp?+?Pro214Glu?+
Tyr218GlyAsn106Glu?+?Ser109Glu?+?Thr195Gln?+?Trp208Pro?+
Pro214GluAsn?68Gln?+?Val103Asp?+?Thr137Gln?+?Ser207Asp?+
Ser222AspThr137Asp?+?Ser207Glu?+?Thr217Gly?+?Leu221Pro?+
Ser222AspGly?69Asp?+?Thr?73Glu?+?Thr111Pro?+?Gly139Asn?+
Ser220AspAsn?66Glu?+?Ser?70Asp?+?Pro214Gly?+?Ser220Glu?+
Leu221SerSer?70Glu?+?Leu104Cys?+?Tyr210Ser?+?Thr215Glu?+
Ser220GluThr167Pro?+?Ser216Glu?+?Ala219Glu?+?Leu221Met?+
Ser222AspVal138Asp?+?Asn166Glu?+?Thr167Asp?+?Ala168Thr?+
Leu221AlaLeu134Pro?+?Serl41Glu?+?Trp208Glu?+?Thr217Ser?+
Ser220GluGly135Glu?+?Tyr171Asn?+?Pro205Gln?+?Trp208Glu?+
Ser220AspTrp112Asn?+?Thr167Glu?+?Ala168Gly?+?Trp208Asp?+
Ser220GluAsn140Asp?+?Pro169Gln?+?Trp208Glu?+?Thr215Gln?+
Ser220GluAsn106Gln?+?Gly136Asp?+?Trp208Glu?+?Thr217Ser?+
Ser220GluAsn106Asp?+?Thr111Asn?+?Thr167Gly?+?Tyr210Asp?+
Ala219AspAsn?66Gln?+?Pro169Asp?+?Tyr171Glu?+?Pro214Asn?+
Gly223GluTrp112Gly?+?Asn163Asp?+?Thr167Glu?+?Ser191Glu?+
Gly223SerTrp112Asp?+?Thr113Ser?+?Ala114Glu?+?Thr217Glu?+
Gly223GlnAsn?66Asp?+?Thr?73Gly?+?Val103Asp?+?Thr111Pro?+
Thr195AsnAsn?68Asp?+?Trp112Met?+?Trp208Asn?+?Pro214Asp?+
Ser220AspAsp105Glu?+?Ser109Glu?+?Asn163Glu?+?Asn166Ser?+
Tyr218GlyGly110Gln?+?Trp112Asp?+?Leu134Pro?+?Pro214Asp?+
Thr217AspGly?67Pro?+?Thr113Glu?+?Gly135Asp?+?Gly162Asp?+
Thr215GlnSer?70Glu?+?Thr195Ser?+?Pro214Ser?+?Ser220Glu?+
Gly223GluGly110Pro?+?Val138Glu?+?Trp208Glu?+?Tyr210Glu?+
Thr217GlyGly108Asn?+?Asn163Glu?+?Ala219Asp?+?Leu221Val?+
Thr224AspThr?73Asp?+?Gly108Asn?+?Ser109Glu?+?Pro214Glu?+
Thr217AsnThr137Asp?+?Gly139Glu?+?Asn170Ser?+?Trp208Cys?+
Tyr210AspTrp112Phe?+?Gly139Glu?+?Tyr213Thr?+?Ala219Glu?+
Leu221GluLeul04Pro?+?Pro169Glu?+?Tyr210Glu?+?Leu221Asp?+
Thr224GlyAsp105Glu?+?Gly165Glu?+?Thr167Gln?+?Ala168Glu?+
Tyr210ProThr137Asp?+?Trp208Asn?+?Tyr218Ser?+?Ser220Asp?+
Ser222AspGly?69Glu?+?Thrll3Gln?+?Thr217Ser?+?Ser220Glu?+
Ser222GluLeu104His?+?Thr113Asp?+?Ser207Asp?+?Thr217Ser?+
Leu221GluAla114Thr?+?Gly135Asp?+?Ser207Asp?+?Thr217Ser?+
Leu221AspGly?69Ser?+?Leu104Asp?+?Asn106Glu?+?Ser191Glu?+
Thr217GlyVal103Ala?+?Tyr171Val?+?Ser207Asp?+?Ser216Asp?+
Tyr218AspGly?69Ser?+?Leu134Ile?+?Gly162Asp?+?Ser207Glu?+
Ser220GluGly?72Pro?+?Thr113Glu?+?Asn166Asp?+?Thr167Asp?+
Thr217GlnAsn166Glu?+?Thr167Asp?+?Ser207Glu?+?Thr217Gly?+
Leu221ValThr111Asn?+?Trp112Glu?+?Val138Gly?+?Asn163Asp?+
Tyr171GluGly?67Pro?+?Asn106Glu?+?Leu134Pro?+?Thr137Asp?+
Pro169GluThr195Glu?+?Ser207Asp?+?Ser220Asp?+?Leu221Val?+
Thr224GlyAsn?68Asp?+?Gly?69Gln?+?Gly162Asp?+?Pro169Ser?+
Gly223AspThr?73Ser?+?Gly165Asn?+?Ser207Asp?+?Tyr210Asp?+
Ser216GluVal103Glu?+?Ala164Asp?+?Asn170Glu?+?Trp208Ala?+
Tyr210IleAla114Thr?+?Ala164Asp?+?Asn170Glu?+?Tyr210Ala?+
Thr215AspAsn?68Glu?+?Gly139Pro?+?Ala164Pro?+?Ser191Asp?+
Pro214GluAsn?68Glu?+?Ala164Glu?+?Gly165Ser?+?Tyr210Gly?+
Pro214AspGly?67Ser?+?Thr167Gly?+?Ser207Glu?+?Ser216Asp?+
Ser220AspAsp105Glu?+?Gly110Asn?+?Ser207Asp?+?Ala219Gly?+
Ser220GluVal103Gly?+?Asn140Asp?+?Ser207Asp?+?Tyr213Asn?+
Ser220AspSer109Glu?+?Gly165Asn?+?Ser207Glu?+?Tyr210Cys?+
Ser220AspGly110Asn?+?Asn140Glu?+?Ser207Glu?+?Thr217Ser?+
Ser220GluGly110Asp?+?Gly136Pro?+?Gly206Gln?+?Ser207Glu?+
Ser220GluThr113Gln?+?Leu134Ile?+?Ser192Glu?+?Thr195Asp?+
Ser220AspGly136Glu?+?Trp208Glu?+?Thr217Gly?+?Leu221Asn?+
Gly223AspSer107Asp?+?Gly110Asp?+?Leu134Ser?+?Asn140Glu?+
Tyr210ThrThr167Glu?+?Trp208Asp?+?Thr217Asn?+?Ala219Asp?+
Gly223AsnGly?69Glu?+?Ala114Asp?+?Thr195Ser?+?Trp208Ser?+
Pro214GluVal103Asp?+?Thr113Glu?+?Phe193Tyr?+?Trp208Asp?+
Ala219ProAsn106Asp?+?Gly136Ser?+?Val138Met?+?Ser191Asp?+
Ser222AspGly135Asp?+?Gly139Glu?+?Tyr210Ala?+?Thr217Ser?+
Ser222AspThr113Asp?+?Asn140Ser?+?Ala203Gln?+?Ser207Glu?+
Tyr210GluGly108Glu?+?Thr113Gln?+?Ser207Glu?+?Tyr210Asp?+
Pro214AsnGly135Glu?+?Asn163Asp?+?Tyr210Met?+?Tyr218Pro?+
Ser220AspAsn163Asp?+?Ala164Thr?+?Ser191Glu?+?Thr217Asp?+
Thr224GlnAsn?68Glu?+?Leu104Asp?+?Val115Thr?+?Ala164Asp?+
Pro214GlnThr?73Gly?+?Ser107Glu?+?Gly108Pro?+?Leu221Glu?+
Thr224AspGly?67Ser?+?Gly162Asp?+?Thr167Asp?+?Ser207Glu?+
Thr217SerGly?67Gln?+?Ser109Glu?+?Val138Ser?+?Pro214Glu?+
Ala219GluSer107Glu?+?Gly135Glu?+?Trp208His?+?Thr217Ser?+
Thr224GluAsn?66Glu?+?Asp105Glu?+?Val138His?+?Ser192Glu?+
Tyr210IleAsn?66Glu?+?Asp105Glu?+?Ala219Gln?+?Ser220Glu?+
Leu221AsnGly?69Ser?+?Ser?70Glu?+?Gly110Glu?+?Thr217Asp?+
Leu221AlaTyr171Glu?+?Ser192Asp?+?Ser207Glu?+?Trp208Pro?+
Tyr210MetGly?67Gln?+?Asp105Glu?+?Ala164Asp?+?Pro169Asn?+
Gly223AspThr?73Asp?+?Ser141Asp?+?Trp208Leu?+?Ser216Glu?+
Thr217ProAsn?66Asp?+?Trp208Gln?+?Ile209Thr?+?Tyr210Val?+
Ser216GluAsn?66Ser?+?Val103Glu?+?Asn106Asp?+?Ser191Glu?+
Tyr210AlaAsn?68Gln?+?Leu134Glu?+?Ser192Glu?+?Leu221Gly?+
Ser222GluSer?70Asp?+?Asp105Glu?+?Gly108Ser?+?Gly139Glu?+
Thr217GlyGly?67Ser?+?Asn106Asp?+?Gly165Gln?+?Ala219Asp?+
Ser222GluAsn106Gln?+?Leu134Met?+?Asn140Asp?+?Ala219Asp?+
Ser222AspGly?69Glu?+?Val103Gln?+?Leu134Asp?+?Thr167Gln?+
Trp208GlyThr137Glu?+?Gly165Glu?+?Tyr210Ser?+?Thr217Ser?+
Leu221ProSer107Asp?+?Gly162Asp?+?Thr167Asp?+?Tyr171Cys?+
Trp208IleAsn106Glu?+?Trp112Asp?+?Leu134Gly?+?Ser141Glu?+
Phe193SerAla114Thr?+?Asn140Asp?+?Phe193Thr?+?Thr217Glu?+
Ser220GluThr113Ser?+?Val115Asp?+?Leu134Val?+?Thr217Asp?+
Ser220GluGly110Asp?+?Asn170Gln?+?Thr217Glu?+?Tyr218Ala?+
Ser220AspThr167Asp?+?Phe193Thr?+?Thr217Asp?+?Ala219Gln?+
Ser220AspGly108Glu?+?Pro214Asn?+?Thr217Glu?+?Ser220Asp?+
Leu221ValAsn106Gln?+?Gly135Glu?+?Val138His?+?Thr217Glu?+
Ser220GluGly110Glu?+?Tyr210Met?+?Thr217Glu?+?Ser220Asp?+
Leu221HisGly?67Glu?+?Ser107Glu?+?Gly110Ser?+?Thr113Glu?+
Thr215SerGly?67Glu?+?Ser107Glu?+?Thr111Pro?+?Ala168His?+
Ser220GluThr111Asp?+?Gly136Asp?+?Trp208Glu?+?Tyr210Met?+
Thr217GlnAsp105Glu?+?Gly162Ser?+?Asn166Asp?+?Ser191Asp?+
Trp208PheAsp105Glu?+?Asn166Glu?+?Ser191Glu?+?Trp208Ala?+
Leu221HisGly?67Glu?+?Val103Glu?+?Ala164Asn?+?Ser207Asp?+
Tyr218AlaGly?72Asn?+?Leu104Asp?+?Asn106Gln?+?Thr113Asp?+
Thr217AspSer?70Asp?+?Gly135Glu?+?Ala168Glu?+?Tyr210Ile?+
Ala219GlyAsn106Gln?+?Ser109Glu?+?Thr113Asp?+?Thr137Glu?+
Trp208AsnAla114Ser?+?Val138Thr?+?Pro169Asn?+?Phe193Asp?+
Trp208GluAsn?68Asp?+?Val138Asp?+?Ala164Gly?+?Ala168Glu?+
Thr217GlyGly?69Asn?+?Val138Asp?+?Ala168Glu?+?Ser207Asp?+
Thr217ProGly110Ser?+?Thr111Gln?+?Ala164Glu?+?Thr215Ser?+
Ser222AspLeu104Ser?+?Gly108Glu?+?Val115Glu?+?Val138His?+
Ser141GluSer?70Glu?+?Ala114Ser?+?Thr137Ser?+?Ser207Asp?+
Ser216AspGly?69Asp?+?Gly110Asp?+?Thr137Glu?+?Pro169Ser?+
Tyr171HisSer?70Asp?+?Thr137Glu?+?Ala164His?+?Trp208Ile?+
Ser220GluSer?70Glu?+?Thr137Glu?+?Thr217Asn?+?Ser220Glu?+
Gly223AsnGly110Gln?+?Trp112Cys?+?Val115Glu?+?Asn140Asp?+
Ser216GluAsn?68Asp?+?Ser109Glu?+?Asn166Gln?+?Trp208Pro?+
Leu221AspThr113Pro?+?Thr167Glu?+?Tyr171Glu?+?Thr217Gln?+
Ser220GluTrp112Ile?+?Leu134His?+?Gly139Asp?+?Gly162Glu?+
Trp208ValGly110Asp?+?Gly162Gln?+?Trp208Ile?+?Tyr210Glu?+
Gly223AspGly?67Asp?+?Thr111Asp?+?Trp208Val?+?Tyr210Ser?+
Ser216GluGly?69Asn?+?Thr?73Glu?+?Asn106Asp?+?Ser141Glu?+
Gly162AsnGly?69Glu?+?Gly135Asn?+?Pro169Asn?+?Trp208Ala?+
Thr217GluAla203Gly?+?Trp208Ala?+?Pro214Glu?+?Ala219Gln?+
Leu221AspThr?73Gly?+?Gly110Glu?+?Pro214Asp?+?Ser220Glu?+
Leu221AsnVal103Ala?+?Thr167Gly?+?Ser192Glu?+?Pro214Glu?+
Ser220AspAsp105Glu?+?Tyr171Gln?+?Pro214Asp?+?Thr217Ser?+
Ser220AspTyr171Val?+?Ser191Asp?+?Trp208Pro?+?Pro214Glu?+
Ser220GluGly?67Asp?+?Gly162Ser?+?Gly206Ser?+?Ser207Glu?+
Thr217GluGly?67Glu?+?Trp112Phe?+?Ser207Asp?+?Thr217Asp?+
Ala219GlnAsn?68Asp?+?Asn163Glu?+?Phe193Met?+?Gly206Ser?+
Leu221GluAsn?66Asp?+?Leu104Ala?+?Ser109Glu?+?Ala168Thr?+
Ser216GluVal138Met?+?Gly139Asp?+?Gly162Ser?+?Ala168Glu?+
Ser220Asp
Table 36
Polycyclic six mutant Asn 66Gln + Gly 67Ser + Gly 69Ser + Leu104Gly + Tyr210Pro + Thr217Glu Ser 70Asp + Gly110Pro + Gly136Gln + Phe193Ser + Trp208Cys + Leu221His Thr113Pro + Gly139Asn + Ser141Glu + Tyr171Pro + Trp208Thr + Leu221Gly Gly 69Gln + Leu104Thr + Ser107Asp + Leu134Thr + Thr215Ser + Leu221Gly Leu104Met + Leu134Ala + Thr137Asp + Trp208Gly + Tyr210Val + Pro214Gly Gly 69Ser + Thr 73Asp + Gly110Ser + Tyr210Leu + Thr215Gly + Thr217Ser Asn 66Ser + Gly 72Gln + Thr 73Pro + Gly110Asp + Trp208Val + Leu221His Thr111Asn + Ala164His + Thr167Glu + Phe193Met + Tyr210Asn + Thr217Gln Asn 66Gln + Thr 73Gly + Thr113Asp + Asn166Ser + Thr167Pro + Tyr210Pro Leu104Met + Pro205Gln + Ser207Asp + Trp208Ala + Thr212Gly + Thr217Pro Leu134Val + Gly165Gln + Trp208Thr + Pro214Gly + Leu221Ile + Thr224Asp Asn 66Ser + Ser109Asp + Ala114Asn + Val115Asn + Trp208Gln + Tyr210Ser Asn106Gln + Ala164Pro + Gly165Ser + Tyr171Ala + Ser220Glu + Thr224Ser Gly110Ser + Gly136Pro + Ile209His + Thr217Gln + Leu221Ile + Thr224Asp Asn 66Gln + Val115Pro + Trp208Asp + Thr217Ser + Leu221Ile + Thr224Pro Gly 67Glu + Thr 73Asn + Asn170Ser + Tyr210Ser + Thr212Gln + Gly223Pro Val103Gly + Ala164Thr + Tyr210His + Ala219His + Ser220Glu + Leu221Gly Thr 73Pro + Asn140Gln + Thr167Asp + Trp208Met + Thr217Gln + Leu221Asn Ser109Asp + Ala164His + Tyr210Pro + Thr212Ser + Gly223Pro + Thr224Asn Gly110Gln + Tyr210Pro + Tyr213Thr + Tyr218Met + Ser220Asp + Leu221His Val138Pro + Ala168Gly + Pro169Gln + Tyr210Ser + Thr217Gln + Ser220Asp Ala114Thr + Thr137Asn + Gly139Ser + Trp208Pro + Pro214Gln + Ser220Glu Val103Met + Thr137Ser + Ala203Ser + Tyr210Thr + Leu221Met + Gly223Ser Leu104Glu + Thr111Ser + Val115His + Gly165Asn + Tyr210Met + Ala219His Gly110Pro + Leu134Pro + Asn166Asp + Asn170Ser + Trp208Asn + Thr217Asn Thr167Glu + Pro169Gly + Asn170Gln + Trp208Gly + Thr215Ser + Leu221Ser Thr111Ser + Thr137Ser + Thr195Gln + Ser207Glu + Tyr210Val + Thr217Pro Asn106Asp + Gly136Pro + Gly162Ser + Trp208Ile + Tyr210Gly + Pro214Gln Ser 70Asp + Gly165Gln + Phe193Asn + Thr195Ser + Trp208Pro + Thr212Ser Gly 72Ser + Ala114Gln + Asn166Gln + Phe193Glu + Tyr210Gly + Thr224Pro Asn 66Ser + Gly136Ser + Gly162Pro + Asn163Ser + Ala164Asp + Ala168Gln Gly 67Pro + Asn106Gln + Ser191Asp + Trp208His + Tyr218His + Leu221Asn Trp112Leu + Ala168Pro + Trp208His + Tyr210Ser + Thr217Gly + Ser220Asp Asn 66Ser + Thr111Gly + Val115Gly + Ala168Ser + Asn170Gln + Pro214Gly Gly110Ser + Trp112Val + Gly162Asn + Thr167Pro + Pro169Gln + Ser216Asp Gly 69Asn + Asn106Ser + Gly139Glu + Asn170Ser + Tyr210Cys + Leu221Gly Gly 69Asn + Ser141Asp + Phe193Asn + Tyr210Ile + Ala219Asn + Leu221Ser Ser109Asp + Pro169Ser + Trp208His + Pro214Asn + Thr215Asn + Thr217Gly Asn 68Asp + Gly162Gln + Ala164His + Trp208Pro + Tyr210Leu + Leu221Val Val103Thr + Gly139Pro + Ala164Thr + Thr217Ser + Leu221Pro + Thr224Pro Gly 69Glu + Gly 72Gln + Thr137Pro + Trp208Ile + Tyr218Pro + Gly223Gln Gly 67Pro + Leu104Cys + Val138Met + Gly139Ser + Ala203Gln + Ala219Asn Trp112Ser + Phe193Ala + Thr217Gly + Tyr218Glu + Leu221Met + Thr224Asn Asn163Gln + Trp208Leu + Tyr210Ser + Thr217Glu + Ala219Gly + Gly223Pro Val103His + Gly110Gln + Gly139Ser + Ser192Asp + Phe193Asn + Thr217Gln Gly108Gln + Pro169Asn + Thr195Ser + Trp208Ala + Thr215Pro + Thr217Glu Ser109Asp + Thr111Asn + Trp112Gln + Thr167Gln + Thr195Gly + Tyr210Asn Gly 72Gln + Trp112Leu + Gly136Asp + Tyr171His + Tyr210Thr + Leu221Ser Gly 69Glu + Ala164Pro + Trp208Val + Tyr210Thr + Tyr218Gln + Thr224Ser Ala114Pro + Leu134Glu + Asn140Ser + Ala164Gln + Phe193Ile + Trp208Asn Asn 66Ser + Val138Met + Gly139Asn + Asn163Gln + Gly165Gln + Tyr210Thr Asn106Gln + Ser191Asp + Phe193Leu + Trp208Val + Pro214Gln + Thr217Ser Ala114Thr + Asn166Ser + Tyr171Gly + Ser191Glu + Ala203Pro + Tyr210Ala Asn 68Gln + Tyr171Asp + Phe193Tyr + Gly206Ser + Tyr210Val + Leu221Thr Leu104Ala + Alal14Ser + Asn163Asp + Thr195Gly + Gly206Gln + Leu221Ala Gly110Asn + Val115Asn + Trp208Cys + Tyr210His + Ala219Thr + Gly223Asp Asn 66Asp + Gly 69Asn + Val115Ala + Ala164Ser + Trp208Gln + Thr217Gln Val115Met + Thr137Ser + Gly162Asn + Asn166Glu + Tyr171His + Pro214Ser Asn106Gln + Gly110Gln + Trp208His + Thr217Pro + Ala219Asp + Ser220Asp Gly 67Asn + Gly 72Asn + Ala114Gly + Asn140Gln + Ser216Asp + Thr217Asp Gly 69Gln + Thr 73Ser + Pro169Gln + Trp208Ile + Ser220Glu + Leu221Asp Asn170Glu + Tyr171Asp + Phe193Ser + Trp208His + Leu221Thr + Thr224Gly Gly 67Ser + Gly 69Glu + Ser 70Glu + Val103Gly + Tyr210Gln + Ala219Asn Trp112Gly + Asn166Ser + Trp208Met + Tyr210Glu + Ser220Glu + Thr224Asn Leu134Pro + Thr195Gly + Trp208Glu + Tyr210Asp + Thr217Ser + Ser220Glu Leu104Gln + Trp112Gln + Tyr171Pro + Trp208Glu + Thr217Gly + Leu221Glu Asp105Glu + Gly108Asp + Gly136Gln + Thr167Gln + Tyr171Gln + Leu221Val Ser107Glu + Ser109Glu + Val138Met + Ala168His + Pro169Gln + Phe193Ser Gly 67Glu + Ser 70Glu + Trp112His + Tyr171Ile + Trp208His + Tyr210Ala Val103Pro + Trp208Glu + Tyr210Ser + Ala219Glu + Ser220Glu + Ser222Asp Ser191Asp + Ser207Glu + Tyr210Ala + Thr215Gly + Thr217Gln + Gly223Ser Asn106Glu + Ser109Asp + Ala168Thr + Tyr171Met + Phe193Ile + Trp208Leu Asn 68Ser + Thr137Gln + Ser191Asp + Ser207Asp + Trp208Asp + Leu221Thr Val103Gln + Val138His + Asn166Asp + Ser192Glu + Trp208His + Leu221Gly Val103Pro + Gly139Pro + Asn163Asp + Gly165Gln + Ala168Glu + Tyr210Leu Asn 68Ser + Thrl13Gln + Leu134Ile + Ser191Glu + Leu221His + Gly223Glu Gly110Gln + Ser207Glu + Trp208Gln + Thr217Pro + Tyr218Gly + Ser220Asp Gly162Ser + Phe193Ala + Trp208Glu + Ile209Ser + Leu221Cys + Gly223Glu Ser 70Asp + Asp105Glu + Gly108Glu + Asn140Gln + Trp208Leu + Thr217Gly Glyl10Asn + Thr137Glu + Pro169Asp + Asn170Ser + Thr195Glu + Tyr210His Asn 68Gln + Gly162Glu + Ala164Thr + Gly165Asp + Tyr171Ala + Ser192Asp Val138Met + Gly139Asn + Asn170Gln + Tyr210Glu + Thr217Asp + Ser220Glu Gly139Ser + Asn163Asp + Ala164Ser + Ser191Asp + Tyr210Gly + Leu221Ala Ser 70Asp + Thr 73Asp + Thr167Ser + Trp208Ser + Thr217Asp + Ala219Asp Asn 66Glu + Leu104Glu + Asp105Glu + Ser107Asp + Leu221Ser + Gly223Pro Asn 66Glu + Thr 73Asp + Gly110Pro + Ala168Gly + Tyr218Val + Leu221Ile Gly 67Asn + Asp105Glu + Asn106Glu + Thr111Glu + Gly165Asn + Thr217Gly Asn 66Asp + Tyr210Ser + Pro214Glu + Thr215Asp + Thr217Gln + Tyr218Asp Thr 73Asn + Ser192Glu + Ala203Thr + Ser207Asp + Trp208Glu + Leu221Glu Val138Gly + Pro169Glu + Ser192Glu + Thr195Glu + Trp208Pro + Thr212Gln Thr 73Asp + Gly108Asn + Leu134Ser + Tyr210Ala + Thr217Gln + Tyr218Glu Thr 73Asn + Ala114Thr + Val138Ser + Gly139Asp + Ser141Glu + Asn170Glu Gly108Gln + Gly135Pro + Gly162Asn + Ser220Glu + Leu221Ala + Gly223Glu Val103Gln + Trp112Cys + Ala164Glu + Trp208Gln + Thr217Gly + Gly223Asp Thr111Gln + Leu134His + Ser191Asp + Phe193Asp + Thr195Gln + Trp208Asp Val103Ser + Leu104Ile + Gly110Glu + Gly136Glu + Ala164Asn + Tyr210Gln Leu134Ser + Thr167Gly + Ser191Glu + Ser220Asp + Leu221Pro + Ser222Asp Gly 69Gln + Trp208Asp + Pro214Glu + Ser220Asp + Ser222Glu + Gly223Asn Ser107Asp + Ser109Glu + Trp112Pro + Gly135Asp + Ala168Thr + Thr212Gly Asn140Ser + Thr167Asp + Trp208Glu + Thr217Asn + Ser220Asp + Leu221Asp Gly135Asp + Gly162Glu + Tyr171Asp + Tyr210Ala + Thr217Ser + Ser222Asp Val115Asp + Tyr210Gln + Ser220Glu + Leu221Asp + Ser222Asp + Gly223Ser Ala114His + Asn166Asp + Tyr171Cys + Tyr210Glu + Ser220Asp + Leu221Asp Val115Cys + Gly139Asn + Ala164Gly + Pro205Asn + Thr217Asp + Ser220Asp Thr167Gln + Tyr210Ile + Thr215Gly + Thr217Asp + Tyr218Asn + Ser220Asp Thr137Ser + Trp208Leu + Tyr210Leu + Thr217Glu + Ser220Asp + Leu221Gly Thr111Asn + Gly135Ser + Trp208Asp + Tyr210Glu + Thr217Glu + Leu221Ala Thr113Asn + Ala114Gly + Thr137Asp + Thr167Asp + Trp208Gln + Gly223Asn Ser 70Asp + Thr 73Glu + Asn163Asp + Thr167Pro + Pro214Glu + Thr217Gly Gly135Glu + Tyr171Asn + Pro205Gln + Ser207Glu + Trp208Glu + Ser220Asp Gly 69Asp + Asp105Glu + Gly108Asp + Ser207Asp + Trp208Thr + Gly223Asn Thr113Gly + Ala114Pro + Tyr210Asp + Pro214Asp + Thr217Gln + Ser220Asp Asn 68Glu + Ser 70Asp + Asp105Glu + Ala114Thr + Gly135Ser + Ser220Asp Thr111Ser + Thr137Glu + Ser207Glu + Trp208Thr + Ser220Glu + Leu221Asp Gly 69Asp + Leu104Asp + Asp105Glu + Asn140Glu + Asn166Ser + Leu221His Thr137Asp + Gly139Glu + Asn170Glu + Trp208Cys + Tyr210Asp + Leu221Thr Gly 67Pro + Trp112Gln + Ser192Asp + Tyr210Ile + Ser220Asp + Ser222Asp Val103Gln + Gly108Asp + Gly135Glu + Thr137Glu + Ala168Gln + Tyr210Asn Val115Asp + Leu134Glu + Asn166Gln + Asn170Asp + Tyr210Val + Thr212Pro Asn 66Asp + Asn 68Ser + Thr167Gln + Ile209Leu + Ser216Asp + Thr217Glu Val103G1u + Gly108Asp + Gly110Glu + Gly165Pro + Thr195Glu + Thr217Gln Asn 66Asp + Ser 70Glu + Thr 73Asp + Ser109Asp + Gly136Pro + Tyr210Ile Gly 69Asp + Ser 70Glu + Asp105Glu + Asn163Glu + Tyr210Met + Thr217Gln Asn 68Gln + Leu134Glu + Ser207Asp + Trp208Pro + Tyr210Asp + Leu221Asp Asn 66Ser + Val115Gly + Gly162Asp + Ser191Glu + Trp208Ile + Thr217Ser Ser 70Glu + Tyr213Thr + Thr217Asn + Tyr218Gly + Ser222Glu + Gly223Asp Trp112Met + Gly165Asp + Pro169Ser + Ser207Glu + Trp208Gly + Ser222Asp Gly 69Ser + Ser109Asp + Gly110Glu + Ala114Gly + Gly136Asp + Phe193Asp Ala164Gln + Gly165Pro + Ser192Asp + Phe193Asp + Ser207Glu + Thr217Asp Asn 68Glu + Thr 73Asn + Gly162Gln + Trp208Gln + Ala219Glu + Ser220Asp Ser 70Glu + Leu134Ser + Gly165Asp + Asn166Asp + Ala168Gly + Ile209Gly Leu104Asp + Asp105Glu + Trp208Gly + Tyr210Glu + Tyr218Ala + Gly223Pro Asn 68Asp + Gly 69Glu + Thr111Asn + Trp112His + Gly136Asn + Pro169Glu Gly108Ser + Asn140Asp + Ser141Glu + Ala164Gln + Ser207Glu + Tyr218Ser Leu104Cys + Gly162Pro + Ser207Glu + Ser216Glu + Thr217Asp + Ala219Thr Ala164Asn + Asn166Asp + Gly206Gln + Tyr210Thr + Ser216Asp + Thr217Asp Gly108Asp + Ser109Asp + Asn166Ser + Thr217Gln + Ser220Asp + Leu221Thr Ser109Asp + Gly110Asp + Val138Ala + Tyr171His + Ala204His + Ser222Glu Asn 68Gln + Thr137Gly + Pro169Asp + Ser207Glu + Trp208Glu + Tyr218Gln Trp112Asp + Thr113Glu + Val138Gly + Ser191Glu + Trp208Pro + Leu221Ser Leu104Gly + Asp105Glu + Asnl06Glu + Gly206Ser + Trp208His + Tyr218Glu Gly108Asp + Leu134Asn + Gly136Gln + Trp208Phe + Ser220Asp + Leu221Asp Gly108Gln + Trp112Tyr + Asn170Glu + Trp208Gln + Ser220Glu + Leu221Glu Gly 72Asn + Asn166Asp + Phe193Ser + Trp208Tyr + Ser220Glu + Leu221Glu Asn 66Glu + Gly 67Glu + Thr111Asn + Thr215Gln + Thr217Asn + Ser220Glu Asn106Asp + Ser107Asp + Gly165Asp + Phe193Val + Trp208Val + Leu221Thr Leu104Val + Gly165Gln + Ser192Asp + Phe193Glu + Tyr210Glu + Leu221Cys Gly136Gln + Pro169Ser + Ser192Asp + Phe193Asp + Trp208Leu + Ser220Glu Ser107Asp + Val115Thr + Thr137Gln + Gly162Asp + Asn163Asp + Ala203His Val103Met + Ser107Glu + Trp208Val + Thr215Glu + Ser216Glu + Gly223Ser Val103Ser + Asn140Asp + Ser141Glu + Tyr210Glu + Ser220Asp + Gly223Asn Asn163Asp + Asn170Glu + Thr195Asn + Ser207Asp + Tyr210Met + Tyr218Pro Asn 66Asp + Gly139Gln + Tyr210Glu + Thr217Ser + Ser220Asp + Thr224Asn Gly 69Asp + Asn106Asp + Gly110Asp + Gly165Asn + Pro169Ser + Thr217Asp Phe193Ile + Thr215Ser + Thr217Glu + Ser220Asp + Leu221Pro + Gly223Glu Val103Gly + Asp105Glu + Thr195Asn + Ser207Asp + Ser222Asp + Gly223Asn Gly 69Asp + Asn140Gln + Ala164His + Ala168Ser + Ser207Asp + Ser222Asp Asn 68Asp + Thr111Asn + Ala114Gly + Gly135Gln + Ser207Glu + Ser222Glu Asn106Asp + Gly139Asn + Gly162Glu + Pro169Ser + Ser191Asp + Thr224Asp Thr113Asp + Ser192Asp + Ser207Glu + Tyr213Thr + Thr215Pro + Ser222Asp Gly 69Pro + Asn163Asp + Thr195Glu + Trp208Ser + Tyr210Glu + Leu221Cys Gly 69Pro + Ser 70Asp + Gly110Ser + Gly135Glu + Asn170Glu + Leu221Ile Gly 69Glu + Ala164His + Thr195Gln + Ser220Glu + Leu221Glu + Thr224Glu Gly 69Gln + Gly136Asp + Val138Asp + Pro169Gly + Asn170Gln + Ser220Glu Gly136Glu + Val138Asp + Thr195Asn + Ser220Glu + Leu221Gly + Gly223Pro Asn 68Gln + Ser107Glu + Ser109Glu + Gly139Gln + Ala164Gln + Ser207Asp Ser107Glu + Ser109Glu + Pro169Gln + Tyr210Met + Thr217Pro + Ser222Asp Gly 67Asp + Ser 70Glu + Val103Ala + Thr111Glu + Tyr210Asn + Pro214Ser Asn 66Glu + Gly 67Asp + Leu134His + Ser191Asp + Ser207Glu + Trp208Thr Asn 66Glu + Val103Asp + Gly108Asn + Asn170Ser + Thr217Asn + Leu221Met Thr 73Glu + Trp112Pro + Asn166Ser + Phe193His + Tyr218Ile + Ser220Glu Val115His + Ser207Glu + Trp208Tyr + Tyr210Leu + Pro214Glu + Leu221Glu Asn 66Gln + Ser107Glu + Ser109Glu + Ser207Glu + Gly223Asp + Thr224Gly Asn 66Glu + Asn 68Asp + Thr 73Gln + Thr195Ser + Ser207Asp + Tyr218Pro Ser 70Asp + Leu104Ile + Asn163Asp + Thr217Gln + Leu221Val + Thr224Glu Gly 67Asp + Val103Glu + Asn106Asp + Ala168Asn + Thr195Glu + Trp208Leu Thr137Gly + Gly162Glu + Phe193Asp + Trp208Asp + Thr217Asn + Tyr218Val Gly135Pro + Gly139Glu + Ser207Glu + Trp208Ala + Tyr210Cys + Gly223Glu Asn106Ser + Thr137Asp + Gly139Glu + Ser141Asp + Ala204Gln + Trp208Glu Trp112Ala + Asn163Glu + Ser192Glu + Trp208Val + Tyr210Glu + Ser220Glu Gly110Asp + Trp112Asp + Tyr210Thr + Ser220Glu + Leu221Met + Ser222Glu Gly 67Asp + Gly 69Asp + Thr 73Pro + Ser109Asp + Trp208Gln + Ser222Asp Asn 66Ser + Val103Glu + Asp105Glu + Trp112His + Ser191Glu + Tyr210Ala Gly 67Glu + Gly 69Asn + Gly162Glu + Ser207Glu + Thr217Asn + Gly223Glu Ser 70Asp + Gly165Asp + Ala168Asp + Trp208Pro + Thr217Gly + Leu221Ile Gly 67Glu + Val103Asn + Gly136Gln + Trp208Pro + Ser216Glu + Leu221Met Gly 67Asn + Gly139Glu + Ser141Glu + Tyr213Gly + Ser220Asp + Leu221Asn Gly 67Glu + Leu104Ser + Tyr210Ser + Ser220Asp + Ser222Glu + Gly223Gln Gly 67Asp + Asn 68Glu + Gly136Asp + Ala168Gln + Pro169Glu + Phe193Asn Asn 66Glu + Gly 69Asp + Asn140Gln + Ser192Asp + Phe193Asp + Tyr210Leu Leu104Asp + Asn106Glu + Asn170Glu + Tyr210Ile + Thr215Ser + Thr224Pro Leu104Asp + Ser107Glu + Gly135Asp + Gly139Asn + Ala164Glu + Thr217Gly Trp112Glu + Gly139Glu + Ala164Glu + Thr195Glu + Thr212Ser + Tyr213Ser Asn 68Asp + Thr111Gly + Thr113Ser + Val138Asp + Asn170Asp + Phe193Ser Asn163Gln + Ala168Asp + Asn170Asp + Ser207Glu + Thr217Gly + Ser220Asp Gly 67Asp + Asn106Glu + Thr113Ser + Gly136Gln + Asn166Glu + Leu221Cys Asn 66Gln + Gly110Asp + Ala114His + Gly136Glu + Thr137Asp + Ser222Glu Gly 67Asp + Asn 68Ser + Gly 72Pro + Gly139Ser + Thr167Glu + Thr195Asp Asn 66Asp + Asn 68Gln + Ser191Glu + Ser207Asp + Trp208Val + Ser220Asp Ser109Glu + Ala114Glu + Leu134Ile + Gly136Ser + Ala219Glu + Ser220Asp Val115Glu + Ala168His + Pro169Asn + Tyr210Asp + Ser216Glu + Ala219Asp Asn 66Glu + Asn106Asp + Asnl70Ser + Trp208Thr + Ser216Asp + Tyr218Gly Gly162Asn + Asn170Asp + Phe193Glu + Tyr210Gln + Ser220Glu + Thr224Asp Gly108Ser + Leu134Pro + Thr137Asp + Pro169Glu + Ser207Glu + Thr217Gly Thr137Asp + Val138Glu + Asn163Glu + Ala164Asn + Ala168Ser + Thr217Glu Gly162Glu + Trp208Glu + Tyr210Val + Thr217Glu + Ser220Glu + Gly223Pro Gly135Asp + Val138Thr + Ser207Asp + Thr217Pro + Tyr218Ile + Ser220Glu Leu104Gly + Ser192Asp + Thr195Asp + Thr217Pro + Ser220Glu + Leu221Asn Asn 66Ser + Gly136Glu + Val138Glu + Trp208Leu + Thr217Asp + Ser220Glu Gly 69Ser + Val103Asp + Ser109Asp + Ser191Asp + Gly206Gln + Tyr210Pro Ala114Gly + Gly162Asp + Pro214Gly + Thr215Asp + Thr217Glu + Ser220Glu Thr137Gln + Gly139Asp + Gly165Pro + Tyr171Glu + Thr217Glu + Ser220Glu Gly 67Glu + Asp105Glu + Asn140Glu + Phe193Gly + Trp208Leu + Leu221Cys Leu104Glu + Trp112Leu + Phe193Leu + Ser207Asp + Trp208Ala + Thr224Asp Ser 70Glu + Thr113Gly + Gly162Ser + Asn163Asp + Ala164Glu + Ser220Asp Gly 69Glu + Ser 70Asp + Thr111Glu + Ser220Asp + Leu221Pro + Gly223Ser Asn 66Gln + Leu104Pro + Gly136Glu + Asn163Asp + Tyr171Ile + Leu221Glu Ser 70Asp + Leu104Glu + Ala168Asn + Pro169Glu + Thr195Asp + Trp208Phe Ser 70Glu + Gly162Glu + Trp208Glu + Thr217Gly + Leu221Thr + Ser222Asp Gly 69Asn + Thr137Glu + Gly139Pro + Asn166Asp + Pro169Asp + Trp208Asp Gly 69Glu + Leu104Glu + Val115Ser + Asn140Ser + Ser192Glu + Pro214Asp Leu104His + Asp105Glu + Val138His + Asn163Asp + Ser192Glu + Thr217Asn Ala114Asn + Asn163Glu + Asn170Ser + Ser192Asp + Ala204Asn + Thr217Asp Asn 68Gln + Thr 73Asp + Ser109Glu + Trp208Phe + Pro214Glu + Ser220Asp Val115Cys + Leu134Asp + Gly135Pro + Ala164Thr + Asn170Asp + Trp208Asp Asn 66Glu + Gly 69Glu + Trp112Gln + Gly135Asn + Gly139Asp + Asn170Glu Thr 73Gly + Ser107Glu + Gly135Asp + Pro169Asp + Trp208Thr + Leu221Asn Gly 67Ser + Ser 70Glu + Gly136Asp + Pro169Asn + Leu221Asp + Gly223Asp Ser 70Asp + Gly110Glu + Val138Ser + Tyr210Val + Leu221Asp + Gly223Asp Asn 66Asp + Leu104Glu + Ser109Glu + Tyr210Asn + Thr217Asn + Ser220Asp Asn 66Glu + Gly 67Asp + Asn163Glu + Ser207Glu + Thr215Gly + Leu221Thr Gly 69Glu + Tyr210Glu + Thr215Asp + Thr217Gln + Tyr218Gln + Ser220Glu Ser 70Asp + Thr137Glu + Ala164His + Thr167Gly + Trp208Asp + Ser220Glu Val138Met + Gly139Gln + Asn140Glu + Ala168Pro + Tyr171Glu + Thr215Glu Val103Gly + Asn106Ser + Ser107Asp + Thr111Asp + Ser222Glu + Gly223Glu Gly 72Gln + Asn106Glu + Gly110Asp + Thr113Glu + Gly135Asn + Ala219Glu Ser109Glu + Thr113Asp + Trp208Ile + Ser220Glu + Leu221Asp + Thr224Ser Gly 67Asn + Ser 70Asp + Gly108Asp + Asn170Glu + Thr215Pro + Leu221Thr Gly 67Asp + Ser107Asp + Thr167Gly + Tyr210Asn + Ser220Asp + Ser222Glu Gly 69Asp + Thr 73Glu + Asn106Gln + Thr111Asn + Val138Glu + Thr217Asp Thr111Asn + Ser191Asp + Thr195Asp + Ala204Thr + Ala219Ser + Ser220Glu Ser109Asp + Ser191Glu + Tyr210Val + Thr215Asn + Leu221Gly + Ser222Glu Thr 73Glu + Leu104Asp + Asn106Gln + Thr195Ser + Ser207Glu + Ser220Asp Asn 66Asp + Thr 73Asp + Leu104Glu + Gly136Gln + Gly162Asp + Leu221Gly Gly 72Asn + Leu104Asp + Asn163Asp + Tyr171Ser + Ser191Glu + Thr217Asn Val115Asp + Gly136Gln + Tyr210Glu + Tyr218Cys + Leu221Asn + Ser222Asp Thr 73Asp + Asn140Ser + Asn163Glu + Thr195Asp + Ser220Asp + Leu221Pro Asn 68Glu + Leu104Asp + Pro169Asn + Trp208Val + Thr217Asn + Gly223Glu Gly110Glu + Thr167Gln + Ser192Glu + Ser207Glu + Trp208Cys + Ser220Asp Val103Gly + Gly136Glu + Asn140Asp + Ser207Asp + Tyr213Asn + Ser220Asp Thr113Asp + Gly136Asp + Thr137Gln + Asn163Glu + Asn166Glu + Trp208Phe Asn 66Glu + Gly 69Glu + Ser109Asp + Ser192Asp + Phe193Val + Tyr218Ala Ser 70Glu + Ser141Asp + Asn163Ser + Trp208Met + Tyr210Pro + Thr215Asp Asp105Glu + Gly110Asn + Thr111Glu + Leu134Ala + Ser141Glu + Phe193Tyr Asn 66Glu + Gly 69Ser + Gly108Asp + Thr111Asp + Thr195Gly + Tyr210Leu Gly165Glu + Tyr171Asn + Ser207Glu + Thr215Glu + Thr217Gly + Thr224Glu Asn 66Gln + Thr 73Ser + Gly139Asn + Pro214Asp + Ser220Asp + Leu221Ile Asn166Glu + Ser192Asp + Trp208Thr + Tyr210Gly + Thr215Asp + Ser222Glu Asn 66Asp + Ser191Asp + Thr215Asn + Ala219Asp + Ser222Asp + Gly223Gln Asp105Glu + Gly108Glu + Thr195Asn + Ile209Leu + Pro214Asp + Ser220Asp Thr111Glu + Val138Asp + Asn163Ser + Tyr218Met + Leu221Glu + Gly223Asp Gly 67Glu + Val138Glu + Ser141Glu + Trp208Ile + Pro214Asn + Thr215Asp Trpl12Leu + Thr113Gln + Gly165Glu + Thr167Asp + Thr217Glu + Ser220Asp Gly 67Gln + Asn 68Asp + Gly 69Asp + Phe193Ala + Ser216Glu + Ser222Glu Ser 70Asp + Val115Glu + Gly162Ser + Ala168Thr + Tyr210Gly + Thr217Asp Ser 70Asp + Gly136Asn + Gly165Glu + Tyr210Asn + Thr217Asp + Leu221His Thr 73Ser + Val103Asn + Ser109Asp + Ser192Asp + Ser207Asp + Trp208Ile Asn106Asp + Ser192Glu + Phe193Pro + Ser207Glu + Thr217Gln + Tyr218Ile Ser141Asp + Thr167Asp + Ala168Asp + Ser191Asp + Ala219Asn + Leu221Thr Asn 66Gln + Ser141Asp + Asn170Ser + Thr217Gln + Ser220Asp + Gly223Asp Thr 73Gly + Asp105Glu + Ala114His + Ser220Glu + Leu221Asn + Gly223Glu Asn106Asp + Asn140Gln + Trp208Ser + Tyr210Cys + Ser220Asp + Gly223Glu Gly 67Gln + Asp105Glu + Ala164Asp + Pro169Asn + Tyr218Leu + Gly223Asp Trp112Val + Asn166Asp + Phe193Gly + Pro214Glu + Ser220Asp + Ser222Glu Gly108Asp + Thr111Asn + Ser192Glu + Thr217Asn + Ala219Glu + Ser220Asp Val103Ser + Val115Asp + Gly139Glu + Asn166Ser + Ser207Glu + Ser220Glu Leu104Asp + Asp105Glu + Asn140Glu + Thr167Asp + Pro214Gly + Ala219Gly Gly 67Asp + Asn 68Asp + Thr111Asp + Ala164Gln + Phe193Ser + Ser207Asp Ser109Glu + Trp208Asp + Ser216Glu + Thr217Asp + Tyr218Asn + Leu221His Ser141Asp + Ala168Glu + Tyr210Met + Ser216Glu + Thr217Asp + Tyr218Ala Ser109Asp + Gly110Asp + Asn166Asp + Asn170Ser + Thr215Ser + Leu221Asp Gly110Glu + Thr167Glu + Ala168Asp + Trp208Met + Ser220Asp + Thr224Gln Asp105Glu + Asn106Asp + Gly165Asp + Thr195Ser + Tyr218Ile + Ser220Asp Asn106Glu + Ser141Asp + Tyr218Ser + Ala219Thr + Ser220Asp + Leu221Glu Thr 73Gln + Thr111Glu + Asn166Asp + Trp208Ser + Ser220Asp + Leu221Asp Ser107Glu + Ala168Asn + Pro169Asn + Ser191Asp + Ser192Asp + Thr217Asp Ala114Glu + Asn166Ser + Thr212Pro + Thr217Glu + Tyr218Asp + Thr224Asp Asn106Glu + Ser107Asp + Gly139Asp + Ala203Asn + Thr217Ser + Ser220Asp Thr113Asn + Gly139Ser + Ser141Glu + Thr215Glu + Ser216Asp + Ser220Asp Gly 69Gln + Asn140Glu + Gly162Glu + Asn163Asp + Tyr210Gln + Ser220Asp Asn 68Asp + Ala114Pro + Gly135Glu + Trp208Asp + Leu221Ile + Gly223Asp Asn 68Asp + Ala164Glu + Trp208Cys + Tyr210Glu + Ala219Thr + Ser220Asp Thr111Asp + Asn166Asp + Asn170Gln + Tyr210Asp + Thr212Ser + Ser220Glu Ser141Glu + Gly165Asp + Trp208Ile + Tyr210Asp + Thr217Gln + Ser220Asp Asn 66Gln + Val103Asp + Gly108Pro + Thr137Glu + Tyr210Glu + Ser220Glu Gly108Glu + Thr137Gln + Asn163Glu + Tyr210Glu + Ser220Asp + Leu221Cys Gly 69Gln + Ser 70Glu + Gly135Glu + Asn163Asp + Thr217Gly + Ser220Asp Asn106Glu + Asn140Glu + Asn163Glu + Asn170Glu + Thr195Asn + Leu221His Asn106Gln + Asn166Asp + Ala168Asn + Asn170Glu + Ser207Glu + Ser220Asp Asn 66Asp + Ser 70Asp + Gly110Gln + Gly136Asp + Pro214Gln + Ser220Asp Asn 68Ser + Pro169Asp + Ser192Glu + Ala219Asp + Gly223Ser + Thr224Asp Thr 73Pro + Gly135Ser + Phe193Glu + Gly206Gln + Tyr210Asp + Thr217Glu Trp112Glu + Val115Gln + Asn170Gln + Thr217Asp + Tyr218Met + Ser220Asp Gly110Asn + Val115Glu + Thr137Gln + Ile209Gly + Thr217Asp + Ser220Glu Gly108Glu + Thr113Gln + Pro214Asn + Thr217Glu + Tyr218Gln + Ser220Asp Gly110Ser + Thr111Gly + Thr113Glu + Phe193Pro + Thr217Glu + Ser220Asp Asn166Glu + Trp208Ile + Tyr210Met + Thr217Glu + Tyr218Val + Ser220Asp Ser 70Glu + Val103Glu + Val115Gln + Pro169Ser + Tyr210Ala + Ser220Asp Asn 66Asp + Ser107Asp + Trp208Met + Tyr210Pro + Ser220Asp + Ser222Glu Gly110Ser + Thr111Asp + Gly135Gln + Gly136Asp + Thr137Asn + Trp208Glu Thr167Asp + Ala168Ser + Pro169Glu + Trp208Thr + Thr215Asp + Leu221Asp Val115Gln + Ala168Gln + Pro169Gln + Phe193Asp + Tyr210Ser + Leu221Asp Asn 66Glu + Gly136Pro + Asn140Gln + Ser191Asp + Trp208Asp + Leu221His Gly136Glu + Gly139Glu + Ser192Asp + Ala203Asn + Trp208Asp + Leu221His Gly 67Asn + Thr113Gln + Thr137Glu + Thr167Asp + Ala219Gln + Leu221Glu Gly 69Asn + Thr 73Asp + Thr111Pro + Asn166Asp + Ser191Asp + Leu221Val Val138Pro + Asn166Glu + Ser191Asp + Tyr218Asn + Ser220Asp + Leu221Gln Asp105Glu + Gly139Asn + Gly165Glu + Trp208Met + Tyr218Thr + Gly223Asp Gly110Asn + Thr111Pro + Ala114Asp + Asn170Asp + Trp208Asp + Tyr210Asp Gly 67Gln + Gly 69Glu + Ser107Asp + Thr167Glu + Ala168Asn + Ser207Asp Gly 69Glu + Gly165Glu + Trp208Cys + Tyr210Cys + Pro214Asp + Ser220Asp Ser 70Glu + Gly 72Gln + Val103Thr + Ser109Glu + Thr113Glu + Ser220Asp Gly 69Pro + Val115Glu + Tyr210Asn + Ser216Asp + Ser220Glu + Ser222Glu Gly136Glu + Trp208Ser + Ser216Asp + Ser220Asp + Leu221Asn + Ser222Asp Leu104Glu + Val115Pro + Gly162Ser + Asn166Asp + Ser220Asp + Ser222Asp Gly 67Glu + Val138Asp + Thr217Ser + Ser220Asp + Leu221His + Ser222Asp Asn 68Asp + Asn170Glu + Gly206Asn + Ser207Asp + Trp208Ile + Leu221AsP Asn106Gln + Ser109Glu + Thr113Asp + Leu134Gln + Thr137Glu + Trp208Asn Asn106Glu + Gly139Gln + Thr167Glu + Pro169Gln + Ser191Asp + Ser207Glu Ser107Glu + Val115Asp + Gly165Asn + Trp208Thr + Tyr218Asp + Ser220Glu Gly72Asn + Asn106Gln + Gly139Asp + Pro169Glu + Trp208Pro + Ser220Glu Val138Asp + Ser141Glu + Pro169Ser + Ser207Glu + Ala219Glu + Leu221Thr Asn106Gln + Ala114Asp + Gly135Asp + Thr195Asn + Ser207Glu + Ser220Asp Ser 70Asp + Asn166Glu + Asn170Gln + Ser216Glu + Thr217Gln + Thr224Gly Gly 69Asp + Asn140Ser + Gly162Pro + Trp208Gly + Thr217Glu + Leu221Asp Asn 68Asp + Ser107Asp + Ala114Gln + Gly162Asp + Thr217Pro + Ser220Glu Ser 70Asp + Thr111Asp + Ile209Met + Thr217Gly + Ser220Glu + Leu221Asn Ser 70Asp + Leu104His + Thr111Gln + Tyr171Ser + Phe193Asp + Ser220Glu Thr113Gly + Gly139Pro + Ser141Glu + Tyr171Glu + Ser192Asp + Ile209Ser Trp112Ala + Thr113Glu + Val138Gln + Ser141Asp + Ser216Asp + Leu221Ser Gly 69Asn + Asn106Asp + Trp112Gly + Gly162Asp + Phe193Glu + Ser220Glu Asn 68Ser + Val103Glu + Asn106Asp + Ala168Pro + Pro169Asp + Pro214Glu Leu104Glu + Ala114Ser + Asn140Ser + Gly165Asp + Ser207Asp + Ser220Glu Asn 68Asp + Ser109Glu + Gly139Glu + Ala204Ser + Leu221His + Gly223Asn Thr111Gly + Val138Pro + Gly139Asp + Ser207Glu + Ser216Glu + Ser220Asp Asn106Asp + Asn170Ser + Ser192Glu + Thr195Asp + Trp208His + Ser220Glu Asn106Asp + Gly162Asp + Asn166Gln + Thr167Asp + Pro214Asp + Ala219Thr Val115Glu + Gly136Glu + Ser207Glu + Tyr218Gly + Ala219Pro + Leu221Pro Gly136Ser + Gly162Asp + Asn163Gln + Ala164His + Ser216Asp + Ser222Glu Asn 68Ser + Thr 73Glu + Asn166Glu + Asn170Gln + Tyr171Gly + Leu221Asp Thr113Glu + Val115Cys + Thr137Glu + Ser191Glu + Thr217Ser + Thr224Glu Gly 67Asp + Ser107Asp + Gly139Asp + Gly165Pro + Thr167Ser + Thr217Glu Thr73Gly + Gly108Asp + Thr137Glu + Gly162Glu + Tyr210Gln + Ser220Asp Leu104Asp + Gly139Pro + Tyr171Asp + Ser191Asp + Ser222Glu + Thr224Ser Thr113Asp + Pro169Glu + Tyr210Gln + Pro214Ser + Ser220Glu + Gly223Asp Gly108Asp + Gly136Glu + Ser141Asp + Thr195Asp + Thr215Ser + Thr217Gln Ser107Asp + Asn163Glu + Pro169Gly + Ser207Asp + Trp208Asn + Gly223Asn Gly110Asp + Asn163Asp + Ser191Asp + Thr195Gln + Tyr210Glu + Thr217Pro Val103Glu + Gly108Asp + Ala203Gly + Trp208Met + Ala219Asp + Thr224Glu Thr73Gln + Thr111Asp + Leu134Asp + Gly136Ser + Asn163Gln + Ser207Asp II. Detergent composition ...
In another embodiment of the present invention, one or more enzyme variant bodies of significant quantity are included in and are used for washing the composition that various needs remove the surface of deproteinize dirt.This cleaning composition comprises the unrestricted form cleaning composition (for example, liquid or particle) that is used for washed hardened surface; The cleaning composition (particle, liquid or strip preparation) that is used for the unrestricted form of laundering of textile fabrics; Dish washing compositions (unrestricted form); The oral cavity of unrestricted form cleaning composition (for example, tooth powder, toothpaste and mouth wash shua preparation); The artificial tooth cleaning composition of unrestricted form (for example, liquid, tablet); Contact lens cleaning composition (for example, liquid, tablet) with unrestricted form.
Except the above-mentioned hot enzyme variant body of this paper, cleaning composition also comprises one or more cleaning composition materials compatible with proteolytic enzyme.Term used herein " cleaning composition material " (for example refers to the particular type of selecting to be used for required cleaning composition and product form, liquid, particle, strip, sprays, bar-shaped, paste, gel) any liquid, solid or gaseous material, this material also should be compatible with the hot enzyme variant body that uses in the composition.Surfacing by considering to be washed, the form (for example using by washing composition) that in use is used for composition required under the wash conditions are specifically selected the cleaning composition material at an easy rate.Term used herein " compatible " refers to proteolytic activity that the cleaning composition material do not reduce hot enzyme variant body in the normal use occasion degree that lost efficacy of proteolytic enzyme as required.Concrete cleaning composition material is illustrated in greater detail hereinafter.
" the enzyme variant body of significant quantity " used herein refers to obtaining the amount of the essential enzyme variant body of enzymic activity required in concrete cleaning composition.This significant quantity is easy to be determined by those skilled in the art, and it is based on many factors, and for example used concrete enzyme variant body, washing are used, the concrete composition of cleaning composition and whether need liquid or anhydrous (for example particle, strip) composition or the like.Cleaning composition preferably contains the 0.0001%-that has an appointment about 10% one or more enzyme variant bodies of the present invention, and more preferably from about 0.001%-is about 1%, also preferred about 0.01%-about 0.1%.Wherein use some examples of the various cleaning composition of enzyme variant body to discuss further hereinafter.All umbers used herein, percentage ratio and ratio are by weight, except as otherwise noted.
" non-woven cleaning composition " used herein comprises hard surface detergent compositions, dish washing compositions, oral cavity cleaning composition, artificial tooth cleaning composition and contact lens cleaning composition.A. the cleaning composition that is used for crust, tableware and fabric
Enzyme variant body of the present invention wherein needing in the various cleaning composition of high bubble and efficient insoluble substrate removal can be used for.Therefore, the enzyme variant body can use to provide the hard surface detergent of full preparation, dish washing compositions, fabric cleaning composition or the like with various conventional ingredients.This composition can be liquid, particle, bar form or the like.This composition can be mixed with the modern times of containing nearly by tensio-active agent weight 30%-60% and " concentrate " washing composition.
Cleaning composition of the present invention optionally and preferably contains the tensio-active agent of various negatively charged ion, nonionic, zwitter-ion or the like.These tensio-active agents exist with the content of about 5%-about 35% of composition usually.
The limiting examples that is used for tensio-active agent of the present invention comprises conventional C 11-C 18Alkylbenzene sulfonate and uncle and random alkyl-sulphate, formula are CH 3(CH 2) x (CHOSO 3 -M +) CH 3And CH 3(CH 2) y (CHOSO 3 -M +) CH 2CH 3C 10-C 18Secondary (2,3) alkyl-sulphate, x and (y+1) be wherein at least about 7, preferably at least about 9 integer, M is a water-soluble cationic, especially sodium, C 10-C 18Alkyl alkoxy sulfate (especially EO 1-5 ethoxy sulfate), C 10-C 18Alkyl alkoxy carboxylate salt (especially EO 1-5 ethoxy carboxylate), C 10-C 18Alkyl poly glucoside and their corresponding sulfation glycan glycosides, and C 12-C 18α-sulfonated fatty acid ester, C 12-C 18Alkyl and alkylphenol alcoxylates (especially ethoxylate and blended ethoxylate/propoxylated glycerine), C 12-C 18Trimethyl-glycine and sultaine (" sultaines "), C 10-C 18Amine oxide or the like.Preferred alkyl alkoxy sulfate of the present invention (AES) and alkyl alkoxy carboxylate salt (AEC).(according to makers-up's needs, it also is preferred using this tensio-active agent and above-mentioned amine oxide and/or trimethyl-glycine or sultaine surfactant mixtures).Other conventional tensio-active agent that uses is listed in normative document.The tensio-active agent that is particularly useful comprises the C in the people's such as Connor of promulgation on March 16th, 1993 US5194639 10-C 18N-methyl glucose amide (glucamides) is classified this paper reference as.
Various other compositions that are used for cleaning composition can be included in the composition of the present invention, and it comprises other activeconstituents, carrier, solubilizing agent, processing aid, dyestuff or pigment, is used for solvent of liquid formulations or the like.Additionally increase foam if desired, in composition, the content with about 1%-about 10% adds whipping agent, for example C usually 10-C 16Alkylolamide.C 10-C 14Monoethanolamine and diglycollic amide have illustrated the type species of this whipping agent.With above-mentioned height bubble cosurfactant, for example to use this class whipping agent together also be favourable for amine oxide, trimethyl-glycine and sultaine.If desired, the dissolved magnesium salts, for example the content that magnesium chloride, sal epsom or the like can about usually 0.1%-about 2% adds so that additional foaming to be provided.
Liquid detergent compositions of the present invention can contain as the water of carrier and other solvent.Low-molecular-weight uncle or secondary alcohol, for example methyl alcohol, ethanol, propyl alcohol and Virahol suit.Single hydroxyl alcohol is preferred for the solubilising of tensio-active agent, but polyvalent alcohol, and the polyvalent alcohol (for example, 1, ammediol, ethylene glycol, glycerine and 1,2-propylene glycol) that for example contains about 6 carbon atoms of the 2-that has an appointment and about 6 hydroxyls of about 2-also can use.It is about 90% that composition can contain the 5%-that has an appointment, this carrier of typically about 10%-about 50%.
Cleaning composition of the present invention will preferably be mixed with in use and operate with aqueous cleaning, washing water will have the pH of about 6.8-about 11.0, therefore final product is prepared in this scope usually. and the technology of control pH in needed scope comprises uses buffer reagent, alkali, acid or the like, is well known by persons skilled in the art.
When preparation hard surface detergent compositions of the present invention and fabric cleaning composition, the content that the makers-up can about by weight 5%-about 50% uses various auxiliary agents.Typical auxiliary agent comprises 1-10 micron zeolite, multi-carboxylate, for example Citrate trianion and oxygen di-succinate, layered silicate, phosphoric acid salt or the like.Other conventional auxiliary agent is listed in standard recipe.
Equally, the makers-up can be in composition, usually with various other the enzymes of the content use of about 0.001%-1% by weight, for example cellulase, lipase, amylase and proteolytic enzyme.Known various washings and enzyme fabric care in the detergent for washing clothes field.
Various bleaching compounds, for example percarbonate, perborate or the like can be usually be used for said composition with the content of about 1%-about 15% by weight.If desired, said composition can also contain bleach activator, for example tetra acetyl ethylene diamine, nonanoly acyloxy benzene sulfonate or the like, and they also are well known in the prior art.Use content to be generally about by weight 1%-about 10%.
Various dirt release agents, especially negatively charged ion oligomer ester type, various sequestrant, especially amino phosphonates do and ethylenediamine disuccinate, various clay stain remover, especially ethoxylation tetraethylene-pentamine, various dispersion agent, especially polyacrylic ester and polyaspartate, various whitening agent, especially negatively charged ion whitening agent, various froth suppressor, especially the content that silane and secondary alcohol, various fabric softener, especially terre verte or the like can about by weight 1%-about 35% is used for composition.The detailed description that this type of conventional substances is arranged in standard recipe and disclosed patent.
In cleaning composition, also can use enzyme stabilizers.Enzyme stabilizers comprises propylene glycol (preferably about 1%-about 10%), sodium formiate (preferably about 0.1%-about 1%) and calcium formiate (preferably about 0.1%-about 1%).L. hard surface detergent compositions
" hard surface detergent compositions " used herein refers to and is used for washed hardened surface, for example liquid of floor, wall, bathroom tile or the like and particle cleaning composition.Hard surface detergent compositions of the present invention contains one or more enzyme variant bodies of the present invention of significant quantity, and it is about 10% to be preferably about 0.001%-by composition organized enzyme weight, and more preferably from about 0.01%-is about 5%, also preferred about 0.05%-about 1%.Except containing one or more enzyme variant bodies, hard surface detergent compositions contains tensio-active agent and water-soluble chelator usually.Yet, at some special product, in the glass cleaner of for example spraying, be not use tensio-active agent sometimes, because they can produce the membranaceous/striped resistates that remains in glass surface.
When existing, surface active agent composition can contain few to 0.1% of composition, but usually composition will to contain the 0.25%-that has an appointment about 10%, the tensio-active agent of 1%-about 5% more preferably from about.
Composition contains the detergent builder of the 0.5%-that has an appointment about 50% usually, is preferably about 1%-about 10%.
The pH value is preferred in the scope of about 8-12.Regulate if desired, can use conventional pH regulator agent, for example sodium hydroxide, yellow soda ash or hydrochloric acid.
In composition, can comprise solvent.Useful solvent comprises, but be not restricted to, glycol ether, for example Diethylene Glycol list hexyl ether, Diethylene Glycol single-butyl ether, ethylene glycol monobutyl ether, ethylene glycol mono hexyl ether, propylene glycol single-butyl ether, dipropylene glycol single-butyl ether, and glycol, for example 2,2.4-trimethylammonium-1,3-pentanediol and 2-ethyl-1, the 3-hexylene glycol.When using, solvent is about 15% with about 0.5%-usually, the content existence of preferably about 3%-about 11%.
In addition, when composition is applied to can use the high volatile volatile solvent when rinsing is not carried out in surperficial rear surface in composition of the present invention with " fully intensity ", for example Virahol or ethanol are to help composition from surperficial rapid evaporation.When using, volatile solvent is present in the composition with the content of about 2%-about 12% usually.
The embodiment of hard surface detergent compositions of the present invention is by following embodiment explanation.
Embodiment 7-12
The liquid hard-surface cleaning composition
Embodiment component 789 10 11 12Gln66Asn 0.05 0.50 0.02 0.03 0.10 0.03Gly206Asn----0.20 0.02Na 2DIDA *EDTA *--2.90 2.90--Trisodium Citrate----2.90 2.90C 12Sodium alkyl benzene sulfonate 1.95-1.95-1.95-C 12Sodium alkyl sulfate-2.20-2.20-2.20C 12(oxyethyl group) * *Sodium sulfate-2.20-2.20-2.20C 12Dimethyl amine oxide compound-0.50-0.50-0.50 cumene sodium sulfonate 1.30-1.30-1.30-hexyl Trivalin SF * *6.30 6.30 6.30 6.30 6.30 6.30 water * * *Balance to 100% *N-Diethylene Glycol-N, the N-Iminodiacetic acid sodium salt *Ethylenediamine-N,N'-diacetic acid(EDDA) four sodium * *Diethylene Glycol list hexyl ether * * *All prescriptions are adjusted to pH7
In embodiment 7-10, replace Gln66Asn with hot enzyme variant body listed among the table 2-36, obtain substantially similar result.
In embodiment 11-12, any combination replacement Gln66Asn and Gly206Asn with hot enzyme variant body listed among the table 2-36 obtain substantially similar result.
Embodiment 13-18
Be used for cleaning of hard surfaces and remove the spray composite that family goes mouldy
Embodiment component 13 14 15 16 17 18Thr111Asn 0.50 0.05 0.60 0.30 0.20 0.30Thr217Gly+Ser222Glu----0.30 0.10 sodium octyl sulfate 2.00 2.00 2.00 2.00 2.00 2.00 lauryl sodium sulfate 4.00 4.00 4.00 4.00 4.00 4.00 NaOH 0.80 0.80 0.80 0.80 0.80 0.80 silicate (sodium) 0.04 0.04 0.04 0.04 0.04 0.04 spices 0.35 0.35 0.35 0.35 0.35 0.35 water balance to 100% product pH are approximately 7.
In embodiment 13-16, replace Thr111Asn with hot enzyme variant body listed among the table 2-36, obtain substantially similar result.
In embodiment 17-18, any combination replacement Thr111Asn and Thr217Gly+Ser222Glu with hot enzyme variant body listed among the table 2-36 obtain substantially similar result.
2. dish washing compositions
In another embodiment of the present invention, dish washing compositions contains one or more enzyme variant bodies of the present invention." dish washing compositions " used herein refers to the form of ownership of the composition that is used for wash dining set, and it comprises, but is not restricted to particle and liquid form.The embodiment of dish washing compositions of the present invention is by following embodiment explanation.
Embodiment 19-24
Dish washing compositions
Embodiment component 19 20 21 22 23 24Gly139Asn 0.05 0.50 0.02 0.40 0.10 0.03Ser207Glu+Tyr210Ser----0.40 0.02+Gly223Asn C 12-C 14N-methyl glucose acyl 0.90 0.90 0.90 0.90 0.90 0.90 amine C 12Oxyethyl group (1) vitriol 12.00 12.00 12.00 12.00 12.00 12.002-methyl undecanoic acids 4.50 4.50 4.50 4.50 4.50 4.50C 12Oxyethyl group (2) carboxylate salt 4.50 4.50 4.50 4.50 4.50 4.50C 12Alcohol ethoxylate (4) 3.00 3.00 3.00 3.00 3.00 3.00C 12Amine oxide 3.00 3.00 3.00 3.00 3.00 3.00 cumene sodium sulfonates 2.00 2.00 2.00 2.00 2.00 2.00 ethanol 4.00 4.00 4.00 4.00 4.00 4.00Mg ++(as magnesium chloride) 0.20 0.20 0.20 0.20 0.20 0.20Ca ++(as calcium chloride) 0.40 0.40 0.40 0.40 0.40 0.40 water balance to 100% product pH regulator to 7.
In embodiment 19-22, replace Gly139Asn with hot enzyme variant body listed among the table 2-36, obtain substantially similar result.
In embodiment 23-24, any combination replacement Gly139Asn and Ser207Glu+Tyr210Ser+Gly223Asn with hot enzyme variant body listed among the table 2-36 obtain substantially similar result.
3. fabric cleaning composition
In another embodiment of the present invention, fabric cleaning composition contains one or more enzyme variant bodies of the present invention." fabric cleaning composition " used herein refers to the form of ownership of the composition that is used for laundering of textile fabrics, and it comprises, but is not restricted to particle, liquid and bar form.Preferred fabric cleaning composition is a liquid form.A. particle fabric cleaning composition
Particle fabric cleaning composition of the present invention contains one or more enzyme variant bodies of the present invention of significant quantity, and it is about 10% to be preferably about 0.001%-by composition organized enzyme weight, and more preferably from about 0.005%-is about 5%, also preferred about 0.01%-about 1%.Except containing one or more enzyme variant bodies, the particle fabric cleaning composition contain usually at least a tensio-active agent, one or more auxiliary agents and, in some cases, SYNTHETIC OPTICAL WHITNER.
The embodiment of particle fabric cleaning composition of the present invention is by following embodiment explanation.
Embodiment 25-28
The particle fabric cleaning composition
Embodiment component 25 26 27 28Ala168Asn 0.10 0.20 0.03 0.05Tyr210Gly+Thr212Pro+Pro--0.02 0.05214Gly+Ser222AspC 13Linear alkylbenzene sulfonate (LAS) 22.00 22.00 22.00 22.00 phosphate (as sodium phosphate trimer) 23.00 23.00 23.00 23.00 sodium carbonate 23.00 23.00 23.00 23.00 sodium metasilicate 14.00 14.00 14.00 14.00 zeolite 8.20 8.20 8.20 8.20 chelating agent (diethylenetriamine pentaacetic acid) 0.40 0.40 0.40 0.40 sodium sulphate 5.50 5.50 5.50 5.50 water balances to 100%
In embodiment 25-26, replace Ala168Asn with hot enzyme variant body listed among the table 2-36, obtain substantially similar result.
In embodiment 27-28, any combination replacement Ala168Asn and Tyr210Gly+Thr212Pro+Pro214Gly+Ser222Asp with hot enzyme variant body listed among the table 2-36 obtain substantially similar result.
Embodiment 29-32
The particle fabric cleaning composition
Embodiment component 29 30 31 32Thr195Pro 0.10 0.20 0.03 0.05Trp208Phe+Tyr213Met+Thr215--0.02 0.05Pro+Ser220Glu+Thr224GlyC 12Sad 4.00 4.00 4.00 4.00C of alkylbenzene sulfonate 12.00 12.00 12.00 12.00 zeolite A (1-10 micron) 26.00 26.00 26.00 26.002-butyl 12-C 14Secondary (2,3) sodium alkyl sulfate 5.00 5.00 5.00 5.00 Trisodium Citrates 5.00 5.00 5.00 5.00 white dyes 0.10 0.10 0.10 0.10 sodium sulfate, 17.00 17.00 17.00 17.00 water and small number of groups balance-dividings to 100%
In embodiment 29-30, replace Thr195Pro with hot enzyme variant body listed among the table 2-36, obtain substantially similar result.
In embodiment 31-32, any combination replacement Thr195Pro and Trp208Phe+Tyr213Met+Thr215Pro+Ser220Glu+Thr224Gly with hot enzyme variant body listed among the table 2-36 obtain substantially similar result.
Embodiment 33-36
The particle fabric cleaning composition
Embodiment component 33 34 35 36Gly67Ser+Gly72Ser 0.10 0.20 0.03 0.05Tyr171Thr--0.02 0.05C 13Linear alkylbenzene sulfonate (LAS) 22.00 22.00 22.00 22.00 phosphate (as sodium phosphate trimer) 23.00 23.00 23.00 23.00 sodium carbonate 23.00 23.00 23.00 23.00 sodium metasilicate 14.00 14.00 14.00 14.00 zeolite 8.20 8 20 8.20 8.20 chelating agent (diethylenetriamine pentaacetic acid) 0.40 0.40 0.40 0.40 sodium sulphate 5.50 5.50 5.50 5.50 water balances to 100%
In embodiment 33-34, replace Gly67Ser+Gly72Ser with hot enzyme variant body listed among the table 2-36, obtain substantially similar result.
In embodiment 35-36, any combination replacement Gly67Ser+Gly72Ser and Tyr171Thr with hot enzyme variant body listed among the table 2-36 obtain substantially similar result.
Embodiment 37-40
The particle fabric cleaning composition
Embodiment component 37 38 39 40Ser192Asp+Phe193Leu+Thr195As 0.10 0.20 0.03 0.05nTyr213Ser+Thr217Gly+Gly223Glu--0.02 0.05C 12Sad 4.00 4.00 4.00 4.00C of alkylbenzene sulfonate 12.00 12.00 12.00 12.00 zeolite A (1-10 micron) 26.00 26.00 26.00 26002-butyl 12-C 14Secondary (2,3) sodium alkyl sulfate 5.00 5.00 5.00 5.00 Trisodium Citrates 5.00 5.00 5.00 5.00 white dyes 0.10 0.10 0.10 0.10 sodium sulfate, 17.00 17.00 17.00 17.00 water and small number of groups balance-dividings to 100%
In embodiment 37-38, replace Ser192Asp+Phe193Leu+Thr195Asn with hot enzyme variant body listed among the table 2-36, obtain substantially similar result.
In embodiment 39-40, any combination replacement Ser192Asp+Phe193Leu+Thr195Asn and Tyr213Ser+Thr217Gly+Gly223Glu with hot enzyme variant body listed among the table 2-36 obtain substantially similar result.
Embodiment 41-42
The particle fabric cleaning composition
Embodiment component 41 42 linear alkylbenzene sulfonates 11.4 10.70 Tallow, beef alkyl-sulphates 1.80 2.40C 14-15Alkyl-sulphate 3.00 3.10C 14-15Polycyclic six mutant Asn 66Gln + Gly 67Ser + Gly 69Ser + Leu104Gly + Tyr210Pro + Thr217Glu Ser 70Asp + Gly110Pro + Gly136Gln + Phe193Ser + Trp208Cys + Leu221His Thr113Pro + Gly139Asn + Ser141Glu + Tyr171Pro + Trp208Thr + Leu221Gly Gly 69Gln + Leu104Thr + Ser107Asp + Leu134Thr + Thr215Ser + Leu221Gly Leu104Met + Leu134Ala + Thr137Asp + Trp208Gly + Tyr210Val + Pro214Gly Gly 69Ser + Thr 73Asp + Gly110Ser + Tyr210Leu + Thr215Gly + Thr217Ser Asn 66Ser + Gly 72Gln + Thr 73Pro + Gly110Asp + Trp208Val + Leu221His Thr111Asn + Ala164His + Thr167Glu + Phe193Met + Tyr210Asn + Thr217Gln Asn 66Gln + Thr 73Gly + Thr113Asp + Asn166Ser + Thr167Pro + Tyr210Pro Leu104Met + Pro205Gln + Ser207Asp + Trp208Ala + Thr212Gly + Thr217Pro Leu134Val + Gly165Gln + Trp208Thr + Pro214Gly + Leu221Ile + Thr224Asp Asn 66Ser + Ser109Asp + Ala114Asn + Val115Asn + Trp208Gln + Tyr210Ser Asn106Gln + Ala164Pro + Gly165Ser + Tyr171Ala + Ser220Glu + Thr224Ser Gly110Ser + Gly136Pro + Ile209His + Thr217Gln + Leu221Ile + Thr224Asp Asn 66Gln + Val115Pro + Trp208Asp + Thr217Ser + Leu221Ile + Thr224Pro Gly 67Glu + Thr 73Asn + Asn170Ser + Tyr210Ser + Thr212Gln + Gly223Pro Val103Gly + Ala164Thr + Tyr210His + Ala219His + Ser220Glu + Leu221Gly Thr 73Pro + Asn140Gln + Thr167Asp + Trp208Met + Thr217Gln + Leu221Asn Ser109Asp + Ala164His + Tyr210Pro + Thr212Ser + Gly223Pro + Thr224Asn Gly110Gln + Tyr210Pro + Tyr213Thr + Tyr218Met + Ser220Asp + Leu221His Val138Pro + Ala168Gly + Pro169Gln + Tyr210Ser + Thr217Gln + Ser220Asp Ala114Thr + Thr137Asn + Gly139Ser + Trp208Pro + Pro214Gln + Ser220Glu Val103Met + Thr137Ser + Ala203Ser + Tyr210Thr + Leu221Met + Gly223Ser Leu104Glu + Thr111Ser + Val115His + Gly165Asn + Tyr210Met + Ala219His Gly110Pro + Leu134Pro + Asn166Asp + Asn170Ser + Trp208Asn + Thr217Asn Thr167Glu + Pro169Gly + Asn170Gln + Trp208Gly + Thr215Ser + Leu221Ser Thr111Ser + Thr137Ser + Thr195Gln + Ser207Glu + Tyr210Val + Thr217Pro Asn106Asp + Gly136Pro + Gly162Ser + Trp208Ile + Tyr210Gly + Pro214Gln Ser 70Asp + Gly165Gln + Phe193Asn + Thr195Ser + Trp208Pro + Thr212Ser Gly 72Ser + Ala114Gln + Asn166Gln + Phe193Glu + Tyr210Gly + Thr224Pro Asn 66Ser + Gly136Ser + Gly162Pro + Asn163Ser + Ala164Asp + Ala168Gln Gly 67Pro + Asn106Gln + Ser191Asp + Trp208His + Tyr218His + Leu221Asn Trp112Leu + Ala168Pro + Trp208His + Tyr210Ser + Thr217Gly + Ser220Asp Asn 66Ser + Thr111Gly + Val115Gly + Ala168Ser + Asn170Gln + Pro214Gly Gly110Ser + Trp112Val + Gly162Asn + Thr167Pro + Pro169Gln + Ser216Asp Gly 69Asn + Asn106Ser + Gly139Glu + Asn170Ser + Tyr210Cys + Leu221Gly Gly 69Asn + Ser141Asp + Phe193Asn + Tyr210Ile + Ala219Asn + Leu221Ser Ser109Asp + Pro169Ser + Trp208His + Pro214Asn + Thr215Asn + Thr217Gly Asn 68Asp + Gly162Gln + Ala164His + Trp208Pro + Tyr210Leu + Leu221Val Val103Thr + Gly139Pro + Ala164Thr + Thr217Ser + Leu221Pro + Thr224Pro Gly 69Glu + Gly 72Gln + Thr137Pro + Trp208Ile + Tyr218Pro + Gly223Gln Gly 67Pro + Leu104Cys + Val138Met + Gly139Ser + Ala203Gln + Ala219Asn Trp112Ser + Phe193Ala + Thr217Gly + Tyr218Glu + Leu221Met + Thr224Asn Asn163Gln + Trp208Leu + Tyr210Ser + Thr217Glu + Ala219Gly + Gly223Pro Val103His + Gly110Gln + Gly139Ser + Ser192Asp + Phe193Asn + Thr217Gln Gly108Gln + Pro169Asn + Thr195Ser + Trp208Ala + Thr215Pro + Thr217Glu Ser109Asp + Thr111Asn + Trp112Gln + Thr167Gln + Thr195Gly + Tyr210Asn Gly 72Gln + Trp112Leu + Gly136Asp + Tyr171His + Tyr210Thr + Leu221Ser Gly 69Glu + Ala164Pro + Trp208Val + Tyr210Thr + Tyr218Gln + Thr224Ser Ala114Pro + Leu134Glu + Asn140Ser + Ala164Gln + Phe193Ile + Trp208Asn Asn 66Ser + Val138Met + Gly139Asn + Asn163Gln + Gly165Gln + Tyr210Thr Asn106Gln + Ser191Asp + Phe193Leu + Trp208Val + Pro214Gln + Thr217Ser Ala114Thr + Asn166Ser + Tyr171Gly + Ser191Glu + Ala203Pro + Tyr210Ala Asn 68Gln + Tyr171Asp + Phe193Tyr + Gly206Ser + Tyr210Val + Leu221Thr Leu104Ala + Alal14Ser + Asn163Asp + Thr195Gly + Gly206Gln + Leu221Ala Gly110Asn + Val115Asn + Trp208Cys + Tyr210His + Ala219Thr + Gly223Asp Asn 66Asp + Gly 69Asn + Val115Ala + Ala164Ser + Trp208Gln + Thr217Gln Val115Met + Thr137Ser + Gly162Asn + Asn166Glu + Tyr171His + Pro214Ser Asn106Gln + Gly110Gln + Trp208His + Thr217Pro + Ala219Asp + Ser220Asp Gly 67Asn + Gly 72Asn + Ala114Gly + Asn140Gln + Ser216Asp + Thr217Asp Gly 69Gln + Thr 73Ser + Pro169Gln + Trp208Ile + Ser220Glu + Leu221Asp Asn170Glu + Tyr171Asp + Phe193Ser + Trp208His + Leu221Thr + Thr224Gly Gly 67Ser + Gly 69Glu + Ser 70Glu + Val103Gly + Tyr210Gln + Ala219Asn Trp112Gly + Asn166Ser + Trp208Met + Tyr210Glu + Ser220Glu + Thr224Asn Leu134Pro + Thr195Gly + Trp208Glu + Tyr210Asp + Thr217Ser + Ser220Glu Leu104Gln + Trp112Gln + Tyr171Pro + Trp208Glu + Thr217Gly + Leu221Glu Asp105Glu + Gly108Asp + Gly136Gln + Thr167Gln + Tyr171Gln + Leu221Val Ser107Glu + Ser109Glu + Val138Met + Ala168His + Pro169Gln + Phe193Ser Gly 67Glu + Ser 70Glu + Trp112His + Tyr171Ile + Trp208His + Tyr210Ala Val103Pro + Trp208Glu + Tyr210Ser + Ala219Glu + Ser220Glu + Ser222Asp Ser191Asp + Ser207Glu + Tyr210Ala + Thr215Gly + Thr217Gln + Gly223Ser Asn106Glu + Ser109Asp + Ala168Thr + Tyr171Met + Phe193Ile + Trp208Leu Asn 68Ser + Thr137Gln + Ser191Asp + Ser207Asp + Trp208Asp + Leu221Thr Val103Gln + Val138His + Asn166Asp + Ser192Glu + Trp208His + Leu221Gly Val103Pro + Gly139Pro + Asn163Asp + Gly165Gln + Ala168Glu + Tyr210Leu Asn 68Ser + Thrl13Gln + Leu134Ile + Ser191Glu + Leu221His + Gly223Glu Gly110Gln + Ser207Glu + Trp208Gln + Thr217Pro + Tyr218Gly + Ser220Asp Gly162Ser + Phe193Ala + Trp208Glu + Ile209Ser + Leu221Cys + Gly223Glu Ser 70Asp + Asp105Glu + Gly108Glu + Asn140Gln + Trp208Leu + Thr217Gly Glyl10Asn + Thr137Glu + Pro169Asp + Asn170Ser + Thr195Glu + Tyr210His Asn 68Gln + Gly162Glu + Ala164Thr + Gly165Asp + Tyr171Ala + Ser192Asp Val138Met + Gly139Asn + Asn170Gln + Tyr210Glu + Thr217Asp + Ser220Glu Gly139Ser + Asn163Asp + Ala164Ser + Ser191Asp + Tyr210Gly + Leu221Ala Ser 70Asp + Thr 73Asp + Thr167Ser + Trp208Ser + Thr217Asp + Ala219Asp Asn 66Glu + Leu104Glu + Asp105Glu + Ser107Asp + Leu221Ser + Gly223Pro Asn 66Glu + Thr 73Asp + Gly110Pro + Ala168Gly + Tyr218Val + Leu221Ile Gly 67Asn + Asp105Glu + Asn106Glu + Thr111Glu + Gly165Asn + Thr217Gly Asn 66Asp + Tyr210Ser + Pro214Glu + Thr215Asp + Thr217Gln + Tyr218Asp Thr 73Asn + Ser192Glu + Ala203Thr + Ser207Asp + Trp208Glu + Leu221Glu Val138Gly + Pro169Glu + Ser192Glu + Thr195Glu + Trp208Pro + Thr212Gln Thr 73Asp + Gly108Asn + Leu134Ser + Tyr210Ala + Thr217Gln + Tyr218Glu Thr 73Asn + Ala114Thr + Val138Ser + Gly139Asp + Ser141Glu + Asn170Glu Gly108Gln + Gly135Pro + Gly162Asn + Ser220Glu + Leu221Ala + Gly223Glu Val103Gln + Trp112Cys + Ala164Glu + Trp208Gln + Thr217Gly + Gly223Asp Thr111Gln + Leu134His + Ser191Asp + Phe193Asp + Thr195Gln + Trp208Asp Val103Ser + Leu104Ile + Gly110Glu + Gly136Glu + Ala164Asn + Tyr210Gln Leu134Ser + Thr167Gly + Ser191Glu + Ser220Asp + Leu221Pro + Ser222Asp Gly 69Gln + Trp208Asp + Pro214Glu + Ser220Asp + Ser222Glu + Gly223Asn Ser107Asp + Ser109Glu + Trp112Pro + Gly135Asp + Ala168Thr + Thr212Gly Asn140Ser + Thr167Asp + Trp208Glu + Thr217Asn + Ser220Asp + Leu221Asp Gly135Asp + Gly162Glu + Tyr171Asp + Tyr210Ala + Thr217Ser + Ser222Asp Val115Asp + Tyr210Gln + Ser220Glu + Leu221Asp + Ser222Asp + Gly223Ser Ala114His + Asn166Asp + Tyr171Cys + Tyr210Glu + Ser220Asp + Leu221Asp Val115Cys + Gly139Asn + Ala164Gly + Pro205Asn + Thr217Asp + Ser220Asp Thr167Gln + Tyr210Ile + Thr215Gly + Thr217Asp + Tyr218Asn + Ser220Asp Thr137Ser + Trp208Leu + Tyr210Leu + Thr217Glu + Ser220Asp + Leu221Gly Thr111Asn + Gly135Ser + Trp208Asp + Tyr210Glu + Thr217Glu + Leu221Ala Thr113Asn + Ala114Gly + Thr137Asp + Thr167Asp + Trp208Gln + Gly223Asn Ser 70Asp + Thr 73Glu + Asn163Asp + Thr167Pro + Pro214Glu + Thr217Gly Gly135Glu + Tyr171Asn + Pro205Gln + Ser207Glu + Trp208Glu + Ser220Asp Gly 69Asp + Asp105Glu + Gly108Asp + Ser207Asp + Trp208Thr + Gly223Asn Thr113Gly + Ala114Pro + Tyr210Asp + Pro214Asp + Thr217Gln + Ser220Asp Asn 68Glu + Ser 70Asp + Asp105Glu + Ala114Thr + Gly135Ser + Ser220Asp Thr111Ser + Thr137Glu + Ser207Glu + Trp208Thr + Ser220Glu + Leu221Asp Gly 69Asp + Leu104Asp + Asp105Glu + Asn140Glu + Asn166Ser + Leu221His Thr137Asp + Gly139Glu + Asn170Glu + Trp208Cys + Tyr210Asp + Leu221Thr Gly 67Pro + Trp112Gln + Ser192Asp + Tyr210Ile + Ser220Asp + Ser222Asp Val103Gln + Gly108Asp + Gly135Glu + Thr137Glu + Ala168Gln + Tyr210Asn Val115Asp + Leu134Glu + Asn166Gln + Asn170Asp + Tyr210Val + Thr212Pro Asn 66Asp + Asn 68Ser + Thr167Gln + Ile209Leu + Ser216Asp + Thr217Glu Val103G1u + Gly108Asp + Gly110Glu + Gly165Pro + Thr195Glu + Thr217Gln Asn 66Asp + Ser 70Glu + Thr 73Asp + Ser109Asp + Gly136Pro + Tyr210Ile Gly 69Asp + Ser 70Glu + Asp105Glu + Asn163Glu + Tyr210Met + Thr217Gln Asn 68Gln + Leu134Glu + Ser207Asp + Trp208Pro + Tyr210Asp + Leu221Asp Asn 66Ser + Val115Gly + Gly162Asp + Ser191Glu + Trp208Ile + Thr217Ser Ser 70Glu + Tyr213Thr + Thr217Asn + Tyr218Gly + Ser222Glu + Gly223Asp Trp112Met + Gly165Asp + Pro169Ser + Ser207Glu + Trp208Gly + Ser222Asp Gly 69Ser + Ser109Asp + Gly110Glu + Ala114Gly + Gly136Asp + Phe193Asp Ala164Gln + Gly165Pro + Ser192Asp + Phe193Asp + Ser207Glu + Thr217Asp Asn 68Glu + Thr 73Asn + Gly162Gln + Trp208Gln + Ala219Glu + Ser220Asp Ser 70Glu + Leu134Ser + Gly165Asp + Asn166Asp + Ala168Gly + Ile209Gly Leu104Asp + Asp105Glu + Trp208Gly + Tyr210Glu + Tyr218Ala + Gly223Pro Asn 68Asp + Gly 69Glu + Thr111Asn + Trp112His + Gly136Asn + Pro169Glu Gly108Ser + Asn140Asp + Ser141Glu + Ala164Gln + Ser207Glu + Tyr218Ser Leu104Cys + Gly162Pro + Ser207Glu + Ser216Glu + Thr217Asp + Ala219Thr Ala164Asn + Asn166Asp + Gly206Gln + Tyr210Thr + Ser216Asp + Thr217Asp Gly108Asp + Ser109Asp + Asn166Ser + Thr217Gln + Ser220Asp + Leu221Thr Ser109Asp + Gly110Asp + Val138Ala + Tyr171His + Ala204His + Ser222Glu Asn 68Gln + Thr137Gly + Pro169Asp + Ser207Glu + Trp208Glu + Tyr218Gln Trp112Asp + Thr113Glu + Val138Gly + Ser191Glu + Trp208Pro + Leu221Ser Leu104Gly + Asp105Glu + Asnl06Glu + Gly206Ser + Trp208His + Tyr218Glu Gly108Asp + Leu134Asn + Gly136Gln + Trp208Phe + Ser220Asp + Leu221Asp Gly108Gln + Trp112Tyr + Asn170Glu + Trp208Gln + Ser220Glu + Leu221Glu Gly 72Asn + Asn166Asp + Phe193Ser + Trp208Tyr + Ser220Glu + Leu221Glu Asn 66Glu + Gly 67Glu + Thr111Asn + Thr215Gln + Thr217Asn + Ser220Glu Asn106Asp + Ser107Asp + Gly165Asp + Phe193Val + Trp208Val + Leu221Thr Leu104Val + Gly165Gln + Ser192Asp + Phe193Glu + Tyr210Glu + Leu221Cys Gly136Gln + Pro169Ser + Ser192Asp + Phe193Asp + Trp208Leu + Ser220Glu Ser107Asp + Val115Thr + Thr137Gln + Gly162Asp + Asn163Asp + Ala203His Val103Met + Ser107Glu + Trp208Val + Thr215Glu + Ser216Glu + Gly223Ser Val103Ser + Asn140Asp + Ser141Glu + Tyr210Glu + Ser220Asp + Gly223Asn Asn163Asp + Asn170Glu + Thr195Asn + Ser207Asp + Tyr210Met + Tyr218Pro Asn 66Asp + Gly139Gln + Tyr210Glu + Thr217Ser + Ser220Asp + Thr224Asn Gly 69Asp + Asn106Asp + Gly110Asp + Gly165Asn + Pro169Ser + Thr217Asp Phe193Ile + Thr215Ser + Thr217Glu + Ser220Asp + Leu221Pro + Gly223Glu Val103Gly + Asp105Glu + Thr195Asn + Ser207Asp + Ser222Asp + Gly223Asn Gly 69Asp + Asn140Gln + Ala164His + Ala168Ser + Ser207Asp + Ser222Asp Asn 68Asp + Thr111Asn + Ala114Gly + Gly135Gln + Ser207Glu + Ser222Glu Asn106Asp + Gly139Asn + Gly162Glu + Pro169Ser + Ser191Asp + Thr224Asp Thr113Asp + Ser192Asp + Ser207Glu + Tyr213Thr + Thr215Pro + Ser222Asp Gly 69Pro + Asn163Asp + Thr195Glu + Trp208Ser + Tyr210Glu + Leu221Cys Gly 69Pro + Ser 70Asp + Gly110Ser + Gly135Glu + Asn170Glu + Leu221Ile Gly 69Glu + Ala164His + Thr195Gln + Ser220Glu + Leu221Glu + Thr224Glu Gly 69Gln + Gly136Asp + Val138Asp + Pro169Gly + Asn170Gln + Ser220Glu Gly136Glu + Val138Asp + Thr195Asn + Ser220Glu + Leu221Gly + Gly223Pro Asn 68Gln + Ser107Glu + Ser109Glu + Gly139Gln + Ala164Gln + Ser207Asp Ser107Glu + Ser109Glu + Pro169Gln + Tyr210Met + Thr217Pro + Ser222Asp Gly 67Asp + Ser 70Glu + Val103Ala + Thr111Glu + Tyr210Asn + Pro214Ser Asn 66Glu + Gly 67Asp + Leu134His + Ser191Asp + Ser207Glu + Trp208Thr Asn 66Glu + Val103Asp + Gly108Asn + Asn170Ser + Thr217Asn + Leu221Met Thr 73Glu + Trp112Pro + Asn166Ser + Phe193His + Tyr218Ile + Ser220Glu Val115His + Ser207Glu + Trp208Tyr + Tyr210Leu + Pro214Glu + Leu221Glu Asn 66Gln + Ser107Glu + Ser109Glu + Ser207Glu + Gly223Asp + Thr224Gly Asn 66Glu + Asn 68Asp + Thr 73Gln + Thr195Ser + Ser207Asp + Tyr218Pro Ser 70Asp + Leu104Ile + Asn163Asp + Thr217Gln + Leu221Val + Thr224Glu Gly 67Asp + Val103Glu + Asn106Asp + Ala168Asn + Thr195Glu + Trp208Leu Thr137Gly + Gly162Glu + Phe193Asp + Trp208Asp + Thr217Asn + Tyr218Val Gly135Pro + Gly139Glu + Ser207Glu + Trp208Ala + Tyr210Cys + Gly223Glu Asn106Ser + Thr137Asp + Gly139Glu + Ser141Asp + Ala204Gln + Trp208Glu Trp112Ala + Asn163Glu + Ser192Glu + Trp208Val + Tyr210Glu + Ser220Glu Gly110Asp + Trp112Asp + Tyr210Thr + Ser220Glu + Leu221Met + Ser222Glu Gly 67Asp + Gly 69Asp + Thr 73Pro + Ser109Asp + Trp208Gln + Ser222Asp Asn 66Ser + Val103Glu + Asp105Glu + Trp112His + Ser191Glu + Tyr210Ala Gly 67Glu + Gly 69Asn + Gly162Glu + Ser207Glu + Thr217Asn + Gly223Glu Ser 70Asp + Gly165Asp + Ala168Asp + Trp208Pro + Thr217Gly + Leu221Ile Gly 67Glu + Val103Asn + Gly136Gln + Trp208Pro + Ser216Glu + Leu221Met Gly 67Asn + Gly139Glu + Ser141Glu + Tyr213Gly + Ser220Asp + Leu221Asn Gly 67Glu + Leu104Ser + Tyr210Ser + Ser220Asp + Ser222Glu + Gly223Gln Gly 67Asp + Asn 68Glu + Gly136Asp + Ala168Gln + Pro169Glu + Phe193Asn Asn 66Glu + Gly 69Asp + Asn140Gln + Ser192Asp + Phe193Asp + Tyr210Leu Leu104Asp + Asn106Glu + Asn170Glu + Tyr210Ile + Thr215Ser + Thr224Pro Leu104Asp + Ser107Glu + Gly135Asp + Gly139Asn + Ala164Glu + Thr217Gly Trp112Glu + Gly139Glu + Ala164Glu + Thr195Glu + Thr212Ser + Tyr213Ser Asn 68Asp + Thr111Gly + Thr113Ser + Val138Asp + Asn170Asp + Phe193Ser Asn163Gln + Ala168Asp + Asn170Asp + Ser207Glu + Thr217Gly + Ser220Asp Gly 67Asp + Asn106Glu + Thr113Ser + Gly136Gln + Asn166Glu + Leu221Cys Asn 66Gln + Gly110Asp + Ala114His + Gly136Glu + Thr137Asp + Ser222Glu Gly 67Asp + Asn 68Ser + Gly 72Pro + Gly139Ser + Thr167Glu + Thr195Asp Asn 66Asp + Asn 68Gln + Ser191Glu + Ser207Asp + Trp208Val + Ser220Asp Ser109Glu + Ala114Glu + Leu134Ile + Gly136Ser + Ala219Glu + Ser220Asp Val115Glu + Ala168His + Pro169Asn + Tyr210Asp + Ser216Glu + Ala219Asp Asn 66Glu + Asn106Asp + Asnl70Ser + Trp208Thr + Ser216Asp + Tyr218Gly Gly162Asn + Asn170Asp + Phe193Glu + Tyr210Gln + Ser220Glu + Thr224Asp Gly108Ser + Leu134Pro + Thr137Asp + Pro169Glu + Ser207Glu + Thr217Gly Thr137Asp + Val138Glu + Asn163Glu + Ala164Asn + Ala168Ser + Thr217Glu Gly162Glu + Trp208Glu + Tyr210Val + Thr217Glu + Ser220Glu + Gly223Pro Gly135Asp + Val138Thr + Ser207Asp + Thr217Pro + Tyr218Ile + Ser220Glu Leu104Gly + Ser192Asp + Thr195Asp + Thr217Pro + Ser220Glu + Leu221Asn Asn 66Ser + Gly136Glu + Val138Glu + Trp208Leu + Thr217Asp + Ser220Glu Gly 69Ser + Val103Asp + Ser109Asp + Ser191Asp + Gly206Gln + Tyr210Pro Ala114Gly + Gly162Asp + Pro214Gly + Thr215Asp + Thr217Glu + Ser220Glu Thr137Gln + Gly139Asp + Gly165Pro + Tyr171Glu + Thr217Glu + Ser220Glu Gly 67Glu + Asp105Glu + Asn140Glu + Phe193Gly + Trp208Leu + Leu221Cys Leu104Glu + Trp112Leu + Phe193Leu + Ser207Asp + Trp208Ala + Thr224Asp Ser 70Glu + Thr113Gly + Gly162Ser + Asn163Asp + Ala164Glu + Ser220Asp Gly 69Glu + Ser 70Asp + Thr111Glu + Ser220Asp + Leu221Pro + Gly223Ser Asn 66Gln + Leu104Pro + Gly136Glu + Asn163Asp + Tyr171Ile + Leu221Glu Ser 70Asp + Leu104Glu + Ala168Asn + Pro169Glu + Thr195Asp + Trp208Phe Ser 70Glu + Gly162Glu + Trp208Glu + Thr217Gly + Leu221Thr + Ser222Asp Gly 69Asn + Thr137Glu + Gly139Pro + Asn166Asp + Pro169Asp + Trp208Asp Gly 69Glu + Leu104Glu + Val115Ser + Asn140Ser + Ser192Glu + Pro214Asp Leu104His + Asp105Glu + Val138His + Asn163Asp + Ser192Glu + Thr217Asn Ala114Asn + Asn163Glu + Asn170Ser + Ser192Asp + Ala204Asn + Thr217Asp Asn 68Gln + Thr 73Asp + Ser109Glu + Trp208Phe + Pro214Glu + Ser220Asp Val115Cys + Leu134Asp + Gly135Pro + Ala164Thr + Asn170Asp + Trp208Asp Asn 66Glu + Gly 69Glu + Trp112Gln + Gly135Asn + Gly139Asp + Asn170Glu Thr 73Gly + Ser107Glu + Gly135Asp + Pro169Asp + Trp208Thr + Leu221Asn Gly 67Ser + Ser 70Glu + Gly136Asp + Pro169Asn + Leu221Asp + Gly223Asp Ser 70Asp + Gly110Glu + Val138Ser + Tyr210Val + Leu221Asp + Gly223Asp Asn 66Asp + Leu104Glu + Ser109Glu + Tyr210Asn + Thr217Asn + Ser220Asp Asn 66Glu + Gly 67Asp + Asn163Glu + Ser207Glu + Thr215Gly + Leu221Thr Gly 69Glu + Tyr210Glu + Thr215Asp + Thr217Gln + Tyr218Gln + Ser220Glu Ser 70Asp + Thr137Glu + Ala164His + Thr167Gly + Trp208Asp + Ser220Glu Val138Met + Gly139Gln + Asn140Glu + Ala168Pro + Tyr171Glu + Thr215Glu Val103Gly + Asn106Ser + Ser107Asp + Thr111Asp + Ser222Glu + Gly223Glu Gly 72Gln + Asn106Glu + Gly110Asp + Thr113Glu + Gly135Asn + Ala219Glu Ser109Glu + Thr113Asp + Trp208Ile + Ser220Glu + Leu221Asp + Thr224Ser Gly 67Asn + Ser 70Asp + Gly108Asp + Asn170Glu + Thr215Pro + Leu221Thr Gly 67Asp + Ser107Asp + Thr167Gly + Tyr210Asn + Ser220Asp + Ser222Glu Gly 69Asp + Thr 73Glu + Asn106Gln + Thr111Asn + Val138Glu + Thr217Asp Thr111Asn + Ser191Asp + Thr195Asp + Ala204Thr + Ala219Ser + Ser220Glu Ser109Asp + Ser191Glu + Tyr210Val + Thr215Asn + Leu221Gly + Ser222Glu Thr 73Glu + Leu104Asp + Asn106Gln + Thr195Ser + Ser207Glu + Ser220Asp Asn 66Asp + Thr 73Asp + Leu104Glu + Gly136Gln + Gly162Asp + Leu221Gly Gly 72Asn + Leu104Asp + Asn163Asp + Tyr171Ser + Ser191Glu + Thr217Asn Val115Asp + Gly136Gln + Tyr210Glu + Tyr218Cys + Leu221Asn + Ser222Asp Thr 73Asp + Asn140Ser + Asn163Glu + Thr195Asp + Ser220Asp + Leu221Pro Asn 68Glu + Leu104Asp + Pro169Asn + Trp208Val + Thr217Asn + Gly223Glu Gly110Glu + Thr167Gln + Ser192Glu + Ser207Glu + Trp208Cys + Ser220Asp Val103Gly + Gly136Glu + Asn140Asp + Ser207Asp + Tyr213Asn + Ser220Asp Thr113Asp + Gly136Asp + Thr137Gln + Asn163Glu + Asn166Glu + Trp208Phe Asn 66Glu + Gly 69Glu + Ser109Asp + Ser192Asp + Phe193Val + Tyr218Ala Ser 70Glu + Ser141Asp + Asn163Ser + Trp208Met + Tyr210Pro + Thr215Asp Asp105Glu + Gly110Asn + Thr111Glu + Leu134Ala + Ser141Glu + Phe193Tyr Asn 66Glu + Gly 69Ser + Gly108Asp + Thr111Asp + Thr195Gly + Tyr210Leu Gly165Glu + Tyr171Asn + Ser207Glu + Thr215Glu + Thr217Gly + Thr224Glu Asn 66Gln + Thr 73Ser + Gly139Asn + Pro214Asp + Ser220Asp + Leu221Ile Asn166Glu + Ser192Asp + Trp208Thr + Tyr210Gly + Thr215Asp + Ser222Glu Asn 66Asp + Ser191Asp + Thr215Asn + Ala219Asp + Ser222Asp + Gly223Gln Asp105Glu + Gly108Glu + Thr195Asn + Ile209Leu + Pro214Asp + Ser220Asp Thr111Glu + Val138Asp + Asn163Ser + Tyr218Met + Leu221Glu + Gly223Asp Gly 67Glu + Val138Glu + Ser141Glu + Trp208Ile + Pro214Asn + Thr215Asp Trpl12Leu + Thr113Gln + Gly165Glu + Thr167Asp + Thr217Glu + Ser220Asp Gly 67Gln + Asn 68Asp + Gly 69Asp + Phe193Ala + Ser216Glu + Ser222Glu Ser 70Asp + Val115Glu + Gly162Ser + Ala168Thr + Tyr210Gly + Thr217Asp Ser 70Asp + Gly136Asn + Gly165Glu + Tyr210Asn + Thr217Asp + Leu221His Thr 73Ser + Val103Asn + Ser109Asp + Ser192Asp + Ser207Asp + Trp208Ile Asn106Asp + Ser192Glu + Phe193Pro + Ser207Glu + Thr217Gln + Tyr218Ile Ser141Asp + Thr167Asp + Ala168Asp + Ser191Asp + Ala219Asn + Leu221Thr Asn 66Gln + Ser141Asp + Asn170Ser + Thr217Gln + Ser220Asp + Gly223Asp Thr 73Gly + Asp105Glu + Ala114His + Ser220Glu + Leu221Asn + Gly223Glu Asn106Asp + Asn140Gln + Trp208Ser + Tyr210Cys + Ser220Asp + Gly223Glu Gly 67Gln + Asp105Glu + Ala164Asp + Pro169Asn + Tyr218Leu + Gly223Asp Trp112Val + Asn166Asp + Phe193Gly + Pro214Glu + Ser220Asp + Ser222Glu Gly108Asp + Thr111Asn + Ser192Glu + Thr217Asn + Ala219Glu + Ser220Asp Val103Ser + Val115Asp + Gly139Glu + Asn166Ser + Ser207Glu + Ser220Glu Leu104Asp + Asp105Glu + Asn140Glu + Thr167Asp + Pro214Gly + Ala219Gly Gly 67Asp + Asn 68Asp + Thr111Asp + Ala164Gln + Phe193Ser + Ser207Asp Ser109Glu + Trp208Asp + Ser216Glu + Thr217Asp + Tyr218Asn + Leu221His Ser141Asp + Ala168Glu + Tyr210Met + Ser216Glu + Thr217Asp + Tyr218Ala Ser109Asp + Gly110Asp + Asn166Asp + Asn170Ser + Thr215Ser + Leu221Asp Gly110Glu + Thr167Glu + Ala168Asp + Trp208Met + Ser220Asp + Thr224Gln Asp105Glu + Asn106Asp + Gly165Asp + Thr195Ser + Tyr218Ile + Ser220Asp Asn106Glu + Ser141Asp + Tyr218Ser + Ala219Thr + Ser220Asp + Leu221Glu Thr 73Gln + Thr111Glu + Asn166Asp + Trp208Ser + Ser220Asp + Leu221Asp Ser107Glu + Ala168Asn + Pro169Asn + Ser191Asp + Ser192Asp + Thr217Asp Ala114Glu + Asn166Ser + Thr212Pro + Thr217Glu + Tyr218Asp + Thr224Asp Asn106Glu + Ser107Asp + Gly139Asp + Ala203Asn + Thr217Ser + Ser220Asp Thr113Asn + Gly139Ser + Ser141Glu + Thr215Glu + Ser216Asp + Ser220Asp Gly 69Gln + Asn140Glu + Gly162Glu + Asn163Asp + Tyr210Gln + Ser220Asp Asn 68Asp + Ala114Pro + Gly135Glu + Trp208Asp + Leu221Ile + Gly223Asp Asn 68Asp + Ala164Glu + Trp208Cys + Tyr210Glu + Ala219Thr + Ser220Asp Thr111Asp + Asn166Asp + Asn170Gln + Tyr210Asp + Thr212Ser + Ser220Glu Ser141Glu + Gly165Asp + Trp208Ile + Tyr210Asp + Thr217Gln + Ser220Asp Asn 66Gln + Val103Asp + Gly108Pro + Thr137Glu + Tyr210Glu + Ser220Glu Gly108Glu + Thr137Gln + Asn163Glu + Tyr210Glu + Ser220Asp + Leu221Cys Gly 69Gln + Ser 70Glu + Gly135Glu + Asn163Asp + Thr217Gly + Ser220Asp Asn106Glu + Asn140Glu + Asn163Glu + Asn170Glu + Thr195Asn + Leu221His Asn106Gln + Asn166Asp + Ala168Asn + Asn170Glu + Ser207Glu + Ser220Asp Asn 66Asp + Ser 70Asp + Gly110Gln + Gly136Asp + Pro214Gln + Ser220Asp Asn 68Ser + Pro169Asp + Ser192Glu + Ala219Asp + Gly223Ser + Thr224Asp Thr 73Pro + Gly135Ser + Phe193Glu + Gly206Gln + Tyr210Asp + Thr217Glu Trp112Glu + Val115Gln + Asn170Gln + Thr217Asp + Tyr218Met + Ser220Asp Gly110Asn + Val115Glu + Thr137Gln + Ile209Gly + Thr217Asp + Ser220Glu Gly108Glu + Thr113Gln + Pro214Asn + Thr217Glu + Tyr218Gln + Ser220Asp Gly110Ser + Thr111Gly + Thr113Glu + Phe193Pro + Thr217Glu + Ser220Asp Asn166Glu + Trp208Ile + Tyr210Met + Thr217Glu + Tyr218Val + Ser220Asp Ser 70Glu + Val103Glu + Val115Gln + Pro169Ser + Tyr210Ala + Ser220Asp Asn 66Asp + Ser107Asp + Trp208Met + Tyr210Pro + Ser220Asp + Ser222Glu Gly110Ser + Thr111Asp + Gly135Gln + Gly136Asp + Thr137Asn + Trp208Glu Thr167Asp + Ala168Ser + Pro169Glu + Trp208Thr + Thr215Asp + Leu221Asp Val115Gln + Ala168Gln + Pro169Gln + Phe193Asp + Tyr210Ser + Leu221Asp Asn 66Glu + Gly136Pro + Asn140Gln + Ser191Asp + Trp208Asp + Leu221His Gly136Glu + Gly139Glu + Ser192Asp + Ala203Asn + Trp208Asp + Leu221His Gly 67Asn + Thr113Gln + Thr137Glu + Thr167Asp + Ala219Gln + Leu221Glu Gly 69Asn + Thr 73Asp + Thr111Pro + Asn166Asp + Ser191Asp + Leu221Val Val138Pro + Asn166Glu + Ser191Asp + Tyr218Asn + Ser220Asp + Leu221Gln Asp105Glu + Gly139Asn + Gly165Glu + Trp208Met + Tyr218Thr + Gly223Asp Gly110Asn + Thr111Pro + Ala114Asp + Asn170Asp + Trp208Asp + Tyr210Asp Gly 67Gln + Gly 69Glu + Ser107Asp + Thr167Glu + Ala168Asn + Ser207Asp Gly 69Glu + Gly165Glu + Trp208Cys + Tyr210Cys + Pro214Asp + Ser220Asp Ser 70Glu + Gly 72Gln + Val103Thr + Ser109Glu + Thr113Glu + Ser220Asp Gly 69Pro + Val115Glu + Tyr210Asn + Ser216Asp + Ser220Glu + Ser222Glu Gly136Glu + Trp208Ser + Ser216Asp + Ser220Asp + Leu221Asn + Ser222Asp Leu104Glu + Val115Pro + Gly162Ser + Asn166Asp + Ser220Asp + Ser222Asp Gly 67Glu + Val138Asp + Thr217Ser + Ser220Asp + Leu221His + Ser222Asp Asn 68Asp + Asn170Glu + Gly206Asn + Ser207Asp + Trp208Ile + Leu221AsP Asn106Gln + Ser109Glu + Thr113Asp + Leu134Gln + Thr137Glu + Trp208Asn Asn106Glu + Gly139Gln + Thr167Glu + Pro169Gln + Ser191Asp + Ser207Glu Ser107Glu + Val115Asp + Gly165Asn + Trp208Thr + Tyr218Asp + Ser220Glu Gly72Asn + Asn106Gln + Gly139Asp + Pro169Glu + Trp208Pro + Ser220Glu Val138Asp + Ser141Glu + Pro169Ser + Ser207Glu + Ala219Glu + Leu221Thr Asn106Gln + Ala114Asp + Gly135Asp + Thr195Asn + Ser207Glu + Ser220Asp Ser 70Asp + Asn166Glu + Asn170Gln + Ser216Glu + Thr217Gln + Thr224Gly Gly 69Asp + Asn140Ser + Gly162Pro + Trp208Gly + Thr217Glu + Leu221Asp Asn 68Asp + Ser107Asp + Ala114Gln + Gly162Asp + Thr217Pro + Ser220Glu Ser 70Asp + Thr111Asp + Ile209Met + Thr217Gly + Ser220Glu + Leu221Asn Ser 70Asp + Leu104His + Thr111Gln + Tyr171Ser + Phe193Asp + Ser220Glu Thr113Gly + Gly139Pro + Ser141Glu + Tyr171Glu + Ser192Asp + Ile209Ser Trp112Ala + Thr113Glu + Val138Gln + Ser141Asp + Ser216Asp + Leu221Ser Gly 69Asn + Asn106Asp + Trp112Gly + Gly162Asp + Phe193Glu + Ser220Glu Asn 68Ser + Val103Glu + Asn106Asp + Ala168Pro + Pro169Asp + Pro214Glu Leu104Glu + Ala114Ser + Asn140Ser + Gly165Asp + Ser207Asp + Ser220Glu Asn 68Asp + Ser109Glu + Gly139Glu + Ala204Ser + Leu221His + Gly223Asn Thr111Gly + Val138Pro + Gly139Asp + Ser207Glu + Ser216Glu + Ser220Asp Asn106Asp + Asn170Ser + Ser192Glu + Thr195Asp + Trp208His + Ser220Glu Asn106Asp + Gly162Asp + Asn166Gln + Thr167Asp + Pro214Asp + Ala219Thr Val115Glu + Gly136Glu + Ser207Glu + Tyr218Gly + Ala219Pro + Leu221Pro Gly136Ser + Gly162Asp + Asn163Gln + Ala164His + Ser216Asp + Ser222Glu Asn 68Ser + Thr 73Glu + Asn166Glu + Asn170Gln + Tyr171Gly + Leu221Asp Thr113Glu + Val115Cys + Thr137Glu + Ser191Glu + Thr217Ser + Thr224Glu Gly 67Asp + Ser107Asp + Gly139Asp + Gly165Pro + Thr167Ser + Thr217Glu Thr73Gly + Gly108Asp + Thr137Glu + Gly162Glu + Tyr210Gln + Ser220Asp Leu104Asp + Gly139Pro + Tyr171Asp + Ser191Asp + Ser222Glu + Thr224Ser Thr113Asp + Pro169Glu + Tyr210Gln + Pro214Ser + Ser220Glu + Gly223Asp Gly108Asp + Gly136Glu + Ser141Asp + Thr195Asp + Thr215Ser + Thr217Gln Ser107Asp + Asn163Glu + Pro169Gly + Ser207Asp + Trp208Asn + Gly223Asn Gly110Asp + Asn163Asp + Ser191Asp + Thr195Gln + Tyr210Glu + Thr217Pro Val103Glu + Gly108Asp + Ala203Gly + Trp208Met + Ala219Asp + Thr224Glu Thr73Gln + Thr111Asp + Leu134Asp + Gly136Ser + Asn163Gln + Ser207Asp II. Detergent composition ...
Embodiment 43-44
The particle fabric cleaning composition
Embodiment component 43 44 straight chain C 12Sodium alkyl benzene sulfonate 6.5 8.0 sodium sulphate 15.0 18.0 zeolite A 26.0 22.0 sodium nitrilo triacetate 5.0 5.0 polyvinylpyrrolidone 0.5 0.7 tetra acetyl ethylene diamine 3.0 3.0 boric acid 4.0-perborate 0.5 1 phenolsulfonate 0.1 0.2Pro205Gly+Trp208Leu+Thr217Gln+Leu 0.4 0.4221Gln+Gly223Gln+Thr224Glu filler (for example, silicate; Carbonate; Spices; Water) to 100 to 100
Embodiment 45
Die mould particle fabric cleaning composition composition weight % alkyl-sulphate 8.0 alkyl ethoxy sulfate 2.0C 25And C 45Mixture 6.0 polyhydroxy fatty acid acid amides 2.5 zeolite 17.0 phyllosilicates/citrate 16.0 carbonate 7.0 maleic acid acrylic copolymer 5.0 dirts of 3 and 7 times of ethoxylations of alcohol are freed polymer 0.4 poly-(4-vinylpridine)-N-oxide 0.1 vinyl imidazole of carboxymethyl cellulose 0.4 and vinyl pyrrolidone copolymer 0.1PEG2000 0.2Asn66Ser+Ser70Glu+Gly72Asn 0.5 lipase 0.2 cellulase 0.2 tetra acetyl ethylene diamine 6.0 percarbonate 22.0 EDDS 0.3 foams in hibitors 3.54; 4 '-two (2-morpholinyl-4-anilino--s-triazine-6-base is amino) 0.25 stilbene-2; 2 '-disulfonic acid disodium 4,4 '-two (2-sulphophenyl vinyl) biphenyl disodium 0.05 water, spices and a small amount of component to 100
Embodiment 46
Particle fabric cleaning composition composition weight % linear alkylbenzene sulfonate 7.6C 16-C 18Alkyl-sulphate 1.3C 14-157 times of ethoxylates of alcohol, the 4.0 coconut alkyl dimethyl hydroxyl ethyl ammonium chloride 1.4 dispersant 0.07 siloxanes liquid 0.8 trisodium citrate 5.0 zeolite 4A 15.0 inferior second triamine of maleic acid acrylic copolymer 4.0 2 pentamethylene phosphonic acids 0.4 perborate 15.0 tetra acetyl ethylene diamine 5.0 terre vertes 10.0 poly-(oxirane) are 0.3Ser109Glu+Thr113Gly 0.4 lipase 0.2 amylase 0.3 cellulase 0.2 sodium metasilicate 3.0 sodium carbonate 10.0 carboxymethyl cellulose 0.2 brightening agent 0.2 water, spices and a small amount of component to 100 (MW300000)
Embodiment 47 particle fabric cleaning composition composition weight % linear alkylbenzene sulfonates 6.92 Tallow, beef alkyl-sulphate 2.05C 14-157 times of ethoxylate 4.4C of alcohol 12-15times ethoxylation 0.16 zeolite 20.2 citrate 5.5 carbonate 15.4 silicate 3.4 maleic acid acrylic copolymer 4.0 carboxymethyl cellulose enzyme 0.31 dirts in alkyl ethoxy sulfate-3 are freed the polymer 0.30Gly135Gln+Val138Asp+Gly139Ser 0.20 lipase 0.36 cellulase 0.13 perborate tetrahydrate 11.64 perborate monohydrate 8.7 inferior second triamine of tetra acetyl ethylene diamine 5.0 2 pentamethyl phosphonic acids 0.38 magnesium sulfate 0.40 brightening agent 0.19 spices, siloxanes, the a small amount of component of foam in hibitors 0.85 is to 100b. liquid fabric washing composition
Liquid fabric cleaning composition of the present invention contains one or more enzyme variant bodies of the present invention of significant quantity, and it is about 5% to be preferably about 0.005%-by composition organized enzyme weight, more preferably about 0.01%-about 1%.This liquid fabric cleaning composition also contains a kind of anion surfactant, lipid acid, water soluble detergent auxiliary agent and water usually.
The embodiment of liquid fabric cleaning composition of the present invention is by following embodiment explanation.
Embodiment 48-52
The liquid fabric cleaning composition
Embodiment component 48 49 50 51 52Asn166Asp+Thr167Asn+ 0.05 0.03 0.30 0.03 0.10Asn170Ser+Tyr171ThrSer191Glu+Ser192Asp+---0.01 0.20Phe193Asp+Thr195ProC 12-C 14Sad 5.00 5.00 5.00 5.00 5.00 Trisodium Citrates of sodium alkyl sulfate 20.00 20.00 20.00 20.00 20.002-butyl 1.00 1.00 1.00 1.00 1.00C 10Alcohol ethoxylate (3) 13.00 13.00 13.00 13.00 13.00 monoethanolamines 2.50 2.50 2.50 2.50 2.50 water/propylene glycol/ethanol (100: 1: 1) balances to 100%
In embodiment 48-50, the hot enzyme variant body listed with table 2-36 replaces Asn166Asp+Thr167Asn+Asn170Ser+Tyr171Thr, obtains substantially similar result.
In embodiment 51-52, any combination replacement Asn166Asp+Thr167Asn+Asn170Ser+Tyr171Thr and Ser191Glu+Ser192Asp+Phe193Asp+Thr195Pro with hot enzyme variant body listed among the table 2-36 obtain substantially similar result.
Embodiment 53-57
The liquid fabric cleaning composition
Embodiment component 53 54 55 56 57Pro205Gln+Gly206Ser+Trp208V 0.05 0.03 0.30 0.03 0.10al+Tyr210Leu+Thr212Asn+Tyr218Met+Ser220GluAsn68Asp+V al138Asp+Ala164---0.01 0.20Gly+Ala168Glu+Thr217GlyC 12-C 14Sad 5.00 5.00 5.00 5.00 5.00 Trisodium Citrates of sodium alkyl sulfate 20.00 20.00 20.00 20.00 20.002-butyl 1.00 1.00 1.00 1.00 1.00C 10Alcohol ethoxylate (3) 13.00 13.00 13.00 13.00 13.00 monoethanolamines 2.50 2.50 2.50 2.50 2.50 water/propylene glycol/ethanol (100: 1: 1) balances to 100%
In embodiment 53-55, replace Pro205Gln+Gly206Ser+Trp208Val+Tyr210Leu+Thr212Asn+Tyr218 Met+Ser220Glu with hot enzyme variant body listed among the table 2-36, obtain substantially similar result.
In embodiment 56-57, any combination with hot enzyme variant body listed among the table 2-36 replaces Pro205Gln+Gly206Ser+Trp208Val+Tyr210Leu+Thr212Asn+Tyr218 Met+Ser220Glu and Asn68Asp+Val138Asp+Ala164Gly+Ala168Glu+Thr217Gly, obtains substantially similar result.
Embodiment 58-59
The liquid fabric cleaning composition
Embodiment component 58 59C 12-14Alkenyl succinic acid 3.0 8.0 citric acid monohydrate 10.0 15.0C 12-15Sodium alkyl sulfate 8.0 8.0C 12-152 times of ethoxylation sodium sulfate-3.0C of alcohol 12-157 times of ethoxylate-8.0C of alcohol 12-15Alcohol 5 times of inferior second triamines five of ethoxylate 8.0-two (methylene phosphonic acid) 0.2-oleic acid 1.8-ethanol 4.0 4.0 propane diols 2.0 2.0Leu134Cys+Thr137Glu+Val138Gly 0.2 02 polyvinylpyrrolidone 1.0 2.0 foam in hibitors 0.15 0.15 NaOH are to pH7.5 perborate 0.5 1 phenolsulfonate 0.1 0.2 peroxidase 0.4 0.1 water and a small amount of component to 100 part
In embodiment 58 and 59, replace Leu134Cys+Thr137Glu+Val138Gly with hot enzyme variant body listed among the table 2-36, obtain substantially similar result.
Embodiment 60-62
The liquid fabric cleaning composition
Example component 606162 citric acids 2.00-2.00 7.10 3.00 3.00 1.93 3.20 3.20 Ethanol 2.22 3.50 3.50 monoethanolamine borate 0.71 1.09 1.091,2 - propylene glycol 7.89 8.00 8.00 1.80 3.00 3.00 cumene sulfonate Sodium hydroxide 0.08 0.08 0.08 silicone defoamer 6.70 3.80 3.80 sodium 1.16 1.18 1.18Gly67Glu Ser70Asp Gly72Ser Thr73Ser 0.0145 - Ile209Ala Ala219Pro-0.0145-Leu216Asn - 0.0145 0.200 0.200 0.200 lipase cellulase soil release polymer -7.50 7.50 0.29 0.06 0.15 0.15 defoamer brightener 36 0.085 0.085 0.095 - brighteners 3-0.05 0.05C12Alkyl benzene sulphonate (ABS) 9.86--C 12-15The many ethoxylations of alkyl (2.5) vitriol 13.80 18.00 18.00C 12Glucamide-5.00 5.00C 12-13Alkyl polyethoxylated (9) 2.00 2.00 2.00 water, spices and small number of groups balance-dividing are to 100%c. strip fabrics cleaning composition
The strip fabrics cleaning composition that is suitable for hand-washing dirty fabric of the present invention contains one or more enzyme variant bodies of the present invention of significant quantity, and it is about 10% to be preferably about 0.001%-by composition organized enzyme weight, more preferably about 0.01%-about 1%.
The embodiment of strip fabrics cleaning composition of the present invention is by following embodiment explanation.
Embodiment 63-66
The strip fabrics cleaning composition
Embodiment component 63 64 65 66Trp112Cys+Thr217Gly 0.3-0.1 0.02Val103Ala+Thr212Ser--0.4 0.03C 12-C 16Sodium alkyl sulfate 20.0 20.0 20.0 20.00C 12-C 14N-methyl glucose amide 5.0 5.0 5.0 5.00C 11-C 13Sodium alkyl benzene sulfonate 10.0 10.0 10.0 10.00 sodium carbonate 25.0 25.0 25.0 25.00 sodium pyrophosphate 7.0 7.0 7.0 7.00 sodium phosphate trimer 7.0 7.0 7.0 7.00 zeolite A (0.1-10 μ) 5.0 5.0 5.0 5.00 carboxymethyl cellulose 0.2 0.2 0.2 0.20 polyacrylate (MW1400) 0.2 0.2 0.2 0.20 coconut alkyl MEA 5.0 5.0 5.0 5.00 brightening agents, spices 0.2 0.2 0.2 0.20 calcium sulfate 1.0 1.0 1.0 1.00 magnesium sulfate 1.0 1.0 1.0 1.00 water 4.0 4.0 4.0 4.00 fillers*Balance to 100% *Can be selected from conventional material, for example lime carbonate, talcum, clay, silicate or the like.
In embodiment 63-64, replace Trp112Cys+Thr217Gly with hot enzyme variant body listed among the table 2-36, obtain substantially similar result.
In embodiment 65-66, any combination replacement Trp112Cys+Thr217Gly and Val103Ala+Thr212Ser with hot enzyme variant body listed among the table 2-36 obtain substantially similar result.
Embodiment 67-70
The strip fabrics cleaning composition
Embodiment component 67 68 69 70Ser109Glu 0.3-0.1 0.02Pro169Glu-0.3 0.4 0.03C 12-C 16Sodium alkyl sulfate 20.0 20.0 20.0 20.0C 12-C 14N-methyl glucose amide 5.0 5.0 5.0 5.00C 11-C 13Sodium alkyl benzene sulfonate 10.0 10.0 10.0 10.00 sodium carbonate 25.0 25.0 25.0 25.00 sodium pyrophosphate 7.0 7.0 7.0 7.00 sodium phosphate trimer 7.0 7.0 7.0 7.00 zeolite A (0.1-10 μ) 5.0 5.0 5.0 5.00 carboxymethyl cellulose 0.2 0.2 0.2 0.20 polyacrylate (MW1400) 0.2 0.2 0.2 0.20 coconut alkyl MEA 5.0 5.0 5.0 5.00 brightening agents, spices 0.2 0.2 0.2 0.20 calcium sulfate 1.0 1.0 1.0 1.00 magnesium sulfate 1.0 1.0 1.0 1.00 water 4.0 4.0 4.0 4.00 fillers*Balance to 100% *Can be selected from conventional material, for example lime carbonate, talcum, clay, silicate or the like.
In embodiment 67, replace Ser109Glu with hot enzyme variant body listed among the table 2-36, obtain substantially similar result.
In embodiment 68, replace Pro169Glu with hot enzyme variant body listed among the table 2-36, obtain substantially similar result.
In embodiment 69-70, any combination replacement Ser109Glu and Pro169Glu with hot enzyme variant body listed among the table 2-36 obtain substantially similar result.B. other cleaning composition
Except above-mentioned hard surface detergent, dishwashing detergent and fabric cleaning composition, one or more enzyme variant bodies of the present invention can add various the needs in other cleaning composition that insoluble hydrolysate separates substrate.Other cleaning composition comprises, but is not restricted to oral cavity cleaning composition, artificial tooth cleaning composition and contact lens cleaning composition.
1. oral cavity cleaning composition
In another embodiment of the present invention, the enzyme variant body of the present invention that comprises one or more pharmaceutically acceptable amounts in composition is to remove the deproteinize dirt from tooth or artificial tooth." oral cavity cleaning composition " used herein refers to the powder that cleans the teeth, toothpaste, tooth gel, tooth powder, mouth wash shua, oral spray, buccal cavity gel, chewing gum, lozenge, sachet, tablet, xanthan gel, prophylaxis pastes, artificial tooth treatment soln or the like.By the weight of composition, it is about 20% that cleaning composition preferably contains the 0.0001-that has an appointment, and more preferably from about 0.001%-is about 10%, one or more enzyme variant body of the present invention and pharmaceutically useful carriers of also preferred about 0.01%-about 5%.Medicine, medicament or inert fraction that " pharmaceutically useful " used herein refers to this term description are suitable for contacting with the tissue of human body and rudimentary animal, and do not have unfavorable toxicity, discomfort, unstable, pungency, anaphylaxis or the like, suitable with beneficial effect/risk-ratio.
It is about 99.99% that the pharmaceutically useful oral cavity wash vehicle component of oral cavity cleaning composition accounts for about 50%-usually by composition weight meter, and preferably about 65%-is about 99.99%, and more preferably from about 65%-about 99%.
Can be included in the cleaning composition of oral cavity of the present invention pharmaceutically useful carrier component and optionally component be well known by persons skilled in the art.Be used for various types of compositions, carrier component and the optional ingredient of oral cavity cleaning composition US5096700 at the Seibel of mandate on March 17th, 1992; Among Benedict, Bush that the US5028414 of the Sampathkumar that on July 2nd, 1991 authorized and on July 2nd, 1991 authorize and the US5028415 of Sunberg, classify this paper reference as.
The embodiment of oral cavity of the present invention cleaning composition illustrates in following embodiment.
Embodiment 71-74
The tooth-cleaning powder composition
Embodiment component 71 72 73 74Tyr218Ala, 2.000 3.500 1.500 2.000 Sorbitol Powders (70% aqueous solution) 35.000 35.000 35.000 35.000PEG-6 *1.000 1.000 1.000 1.000 silicon oxide tooth abrasive materials *20.000 20.000 20.000 20.000 sodium fluoride 0.243 0.243 0.243 0.243 titanium dioxide 0.500 0.500 0.500 0.500 saccharin sodium 0.286 0.286 0.286 0.286 sodium alkyl sulfate (27.9% aqueous solution) 4.000 4.000 4.000 4.000 spices 1.040 1.040 1.040 1.040 carboxy vinyl polymers* *0.300 0.300 0.300 0.300Carrageenan * * *0.800 0.800 0.800 0.800 water balance to 100% *The polyoxyethylene glycol of PEG-6=molecular weight 600. *The sedimentary silicon oxide Zeodent119 that provides by J.M.Huber * *The Carbopol that provides by B.F.Goodrich Chemical Company * * *The lota Carrageenan that provides by Hercules Chemical Company.
In embodiment 71-74, replace Tyr218Ala with hot enzyme variant body listed among the table 2-36, obtain substantially similar result.
Embodiment 75-78
Mouthwash agent composition
Embodiment component 75 76 77 78Ala164His+Ser220Glu 3.00 7.50 1.00 5.00SDA40 alcohol 8.00 8.00 8.00 8.00 spices 0.08 0.08 0.08 0.08 emulsification profit 0.08 0.08 0.08 0.08 sodium fluoride 0.05 0.05 0.05 0.05 glycerine 10.00 10.00 10.00 10.00 sweetener 0.02 0.02 0.02 0.02 benzoic acid 0.05 0.05 0.05 0.05 NaOH 0.20 0.20 0.20 0.20 dyestuff 0.04 0.04 0.04 0.04 water balances to 100% are in embodiment 75-78; Replace Ala164His+Ser220Glu with hot enzyme variant listed in table 2-36, obtain substantially similar result.
Embodiment 79-82
Lozenge composition
Embodiment component 79 80 81 82Leu221Val+Thr224Gln 0.01 0.03 0.10 0.02 D-sorbite 17.50 17.50 17.50 17.50 mannitol 17.50 17.50 17.50 17.50 starch 13.60 13.60 13.60 13.60 sweetener 1.20 1.20 1.20 1.20 spices 11.70 11.70 11.70 11.70 pigment 0.10 0.10 0.10 0.10 corn syrup balances to 100%
In embodiment 79-82, replace Leu221Val+Thr224Gln with hot enzyme variant body listed among the table 2-36, obtain substantially similar result.
Embodiment 83-86
The Chewing gum composition
Embodiment component 83 84 85 86Ser191Asp+Phe193Ile+Thr195Gly 0.03 0.02 0.10 0.05 Sorbitol Powder crystallization 38.44 38.40 38.40 38.40Palija-T gum *20.00 20.00 20.00 20.00 Sorbitol Powders (70% aqueous solution), 22.00 22.00 22.00 22.00 mannitols, 10.00 10.00 10.00 10.00 glycerine, 7.56 7.56 7.56 7.56 spices 1.00 1.00 1.00 1.00 *L.A.Dreyfus Company provides.
In embodiment 83-86, replace Ser191Asp+Phe193Ile+Thr195Gly with hot enzyme variant body listed among the table 2-36, obtain substantially similar result.
2. the artificial tooth cleaning composition is in another embodiment of the present invention, and the artificial tooth cleaning composition that is used for washing artificial tooth outside the oral cavity contains one or more enzyme variant bodies of the present invention.This artificial tooth cleaning composition contains one or more enzyme variant bodies of significant quantity, preferably press composition weight meter, about 0.0001-is about 50%, and more preferably from about 0.001%-about 35%, one or more of also preferably about 0.01%-about 20% enzyme variant body of the present invention and artificial tooth wash vehicle.Various artificial tooth cleaning composition prescriptions are (referring to the US5055305 of for example Young, classifying this paper reference as) well known in the prior art as effervescent tablet or the like, are generally suitable for adding one or more enzyme variant bodies so that remove the deproteinize dirt from artificial tooth.
The embodiment of artificial tooth cleaning composition of the present invention is by following embodiment explanation.
Embodiment 87-90
Double-deck effervesce artificial tooth washing sheet
Acid layer Gly135Gln+Gly139Asn+ 1.0 1.5 0.01 0.05Asn140Gln+Ser141Asp tartaric acid 24.0 24.0 24.00 24.00 sodium carbonate 4.0 4.0 4.00 4.00 sulfamic acid 10.0 10.0 10.00 10.00PEG20000 4.0 4.0 4.00 4.00 sodium acid carbonate 24.5 24.5 24.50 24.50 potassium peroxydisulfate 15.0 15.0 15.00 15.00 acidic sodium pyrophosphate 7.0 7.0 7.00 7.00 pyrolysis silica 2.0 2.0 2.00 2.00TAED of embodiment component 87 88 89 90*7.0 7.0 7.00 7.00 castor-oil plant acyl group sulfosuccinate 0.5 0.5 0.50 0.50 spices 1.0 1.0 1.00 1.00 alkaline layer sodium perborate list hydrate 32.0 32.0 32.00 32.00 sodium acid carbonate 19.0 19.0 19.00 19.00EDTA 3.0 3.0 3.00 3.00 sodium phosphate trimer 12.0 12.0 12.00 12.00PEG20000 2.0 2.0 2.00 2.0 potassium peroxydisulfate 26.0 26.0 26.00 26.00 sodium carbonate 2.0 2.0 2.00 2.00 pyrolysis silica 2.0 2.0 2.00 2.00 dyestuffs/spices 2.0 2.0 2.00 2.00*Tetra acetyl ethylene diamine
In embodiment 87-90, replace Gly135Gln+Gly139Asn+Asn140Gln+Ser141Asp with hot enzyme variant body listed among the table 2-36, obtain substantially similar result.
2. contact lens cleaning composition
In another embodiment of the present invention, the contact lens cleaning composition contains one or more enzyme variant bodies of the present invention.This contact lens cleaning composition contains one or more enzyme variant bodies of significant quantity, preferably press composition weight meter, about 0.01-is about 50%, and more preferably from about 0.01%-about 20%, one or more of also preferably about 1%-about 5% enzyme variant body of the present invention and contact lens wash vehicle.Various contact lens cleaning composition prescriptions, for example tablet, liquid or the like are known (referring to the Davies that for example authorized on September 5th, 1989, Meaken and Rees, US4863627 in the prior art; The Huth that on May 24th, 1988 authorized once more, Lam and Kirai, USRe32672; The Schafer that authorized on September 2nd, 1986 is arranged, US4609493; Ogunbiyi and Smith that on September 1st, 1987 authorized, US4690793; The Ogunbiyi that on September 30th, 1986 authorized, Riedhammer and Smiht, US4614549; With the Ogata that authorized on August 25th, 1981, US4285738; All classify this paper reference as), be generally suitable for adding one or more enzyme variant bodies of the present invention so that remove the deproteinize dirt from contact lens.
The embodiment of contact lens cleaning composition of the present invention is by following embodiment explanation.
Embodiment 91-94
Enzymolysis contact lens washing soln
Embodiment component 91 92 93 94Leu221Gln 0.01 0.5 0.1 2.0 glucose 50.00 50.0 50.0 50.0 non-ionic surface active agents (polyoxyethylene-2.00 2.0 2.0 2.0 polyoxypropylene copolymers) anion surfactants (polyoxyethylene-1.00 1.0 1.0 1.0 alkyl phenyl ether sodium sulfovinates) sodium chloride 1.00 1.0 1.0 1.0 borax 0.30 0.3 0.3 0.3 water balances to 100%
In embodiment 91-94, replace Leu221Gln with hot enzyme variant body listed among the table 2-36, obtain substantially similar result.
Although described specific embodiments of the present invention, obviously those skilled in the art can make various changes and improvements of the present invention and can not run counter to the spirit and scope of the present invention.In the appended claims, scope of the present invention has covered all these improvement.

Claims (9)

1.具有热酶(thermitase)野生型氨基酸序列的修饰氨基酸序列的热酶变异体，野生型氨基酸序列包括第一环区域、第二环区域、第三环区域、第四环区域、第五环区域和第六环区域；其中修饰的氨基酸序列在一个或多个环区域内的一个或多个位点上含有取代基；其中1. A thermal enzyme variant having a modified amino acid sequence of the wild-type amino acid sequence of thermitase, the wild-type amino acid sequence comprising a first loop region, a second loop region, a third loop region, a fourth loop region, and a fifth loop region and the sixth loop region; wherein the modified amino acid sequence contains a substituent at one or more positions within one or more loop regions; wherein A.当取代发生在第一环区域中时，取代发生在位点66、69、70、72或73的一个或多个上；其中A. When the substitution occurs in the first loop region, the substitution occurs at one or more of positions 66, 69, 70, 72, or 73; wherein a.当取代发生在位点66时，取代氨基酸是Asn；a. When the substitution occurs at position 66, the substituting amino acid is Asn; b.当取代发生在位点69时，取代氨基酸是Gln；b. When the substitution occurs at position 69, the substituting amino acid is Gln; c.当取代发生在位点70时，取代氨基酸是Asn、Asp、Gln、Glu、Pro或Ser；c. When the substitution occurs at position 70, the substituting amino acid is Asn, Asp, Gln, Glu, Pro or Ser; d.当取代发生在位点72时，取代氨基酸是Asn、Asp、Gln、Glu、Pro或Ser；d. When the substitution occurs at position 72, the substituting amino acid is Asn, Asp, Gln, Glu, Pro or Ser; e.当取代发生在位点73时，取代氨基酸是Asn、Asp、Gln、Glu、Pro或Ser；e. When the substitution occurs at position 73, the substituting amino acid is Asn, Asp, Gln, Glu, Pro or Ser; B.当取代发生在第二环区域中时，取代发生在位点103、104、105、106、108、110、112、113或114的一个或多个上；其中B. When the substitution occurs in the second loop region, the substitution occurs at one or more of positions 103, 104, 105, 106, 108, 110, 112, 113, or 114; wherein a.当取代发生在位点103时，取代氨基酸是Ala、Asn、Asp、Cys、Gln、Glu、Gly、His、Met、Pro、Ser或Thr；a. When the substitution occurs at position 103, the substituting amino acid is Ala, Asn, Asp, Cys, Gln, Glu, Gly, His, Met, Pro, Ser or Thr; b.当取代发生在位点104时，取代氨基酸是Ala、Asn、Asp、Cys、Gln、Gly、His、Ile、Met、Pro或Ser；b. When the substitution occurs at position 104, the substituting amino acid is Ala, Asn, Asp, Cys, Gln, Gly, His, Ile, Met, Pro or Ser; c.当取代发生在位点105时，取代氨基酸是Glu；c. When the substitution occurs at position 105, the substituting amino acid is Glu; d.当取代发生在位点106时，取代氨基酸是Gln；d. When the substitution occurs at position 106, the substituting amino acid is Gln; e.当取代发生在位点108时，取代氨基酸是Asn、Gln、Pro或Ser；e. When the substitution occurs at position 108, the substituting amino acid is Asn, Gln, Pro or Ser; f.当取代发生在位点110时，取代氨基酸是Asn、Asp、Gln、Glu、Pro或Ser；f. When the substitution occurs at position 110, the substituting amino acid is Asn, Asp, Gln, Glu, Pro or Ser; g.当取代发生在位点112时，取代氨基酸是Asn、Asp、Cys、Gln、Glu、His、Ile、Met、Phe、Pro、Thr或Tyr；g. When the substitution occurs at position 112, the substituting amino acid is Asn, Asp, Cys, Gln, Glu, His, Ile, Met, Phe, Pro, Thr or Tyr; h.当取代发生在位点113时，取代氨基酸是Asn、Asp、Gln、Glu、Pro或Ser；和h. When the substitution occurs at position 113, the substituting amino acid is Asn, Asp, Gln, Glu, Pro or Ser; and i.当取代发生在位点114时，取代氨基酸是Asn、Asp、Gln、Glu、Gly、His、Pro、Ser或Thr；i. When the substitution occurs at position 114, the substituting amino acid is Asn, Asp, Gln, Glu, Gly, His, Pro, Ser or Thr; C.当取代发生在第三环区域中时，取代发生位点134、135、136、137、138、139或141的一个或多个上；其中C. When the substitution occurs in the third loop region, the substitution occurs at one or more of positions 134, 135, 136, 137, 138, 139, or 141; wherein a.当取代发生在位点134时，取代氨基酸是Ala、Asn、Cys、Gln、Gly、His、Met、Pro、Ser、Thr或Val；a. When the substitution occurs at position 134, the substituting amino acid is Ala, Asn, Cys, Gln, Gly, His, Met, Pro, Ser, Thr or Val; b.当取代发生在位点135时，取代氨基酸是Asn、Asp、Gln、Glu、Pro或Ser；b. When the substitution occurs at position 135, the substituting amino acid is Asn, Asp, Gln, Glu, Pro or Ser; c.当取代发生在位点136时，取代氨基酸是Pro；c. When the substitution occurs at position 136, the substituting amino acid is Pro; d.当取代发生在位点137时，取代氨基酸是Asn、Asp、Gln、Glu或Ser；d. When the substitution occurs at position 137, the substituting amino acid is Asn, Asp, Gln, Glu or Ser; e.当取代发生在位点138时，取代氨基酸是Ala、Asn、Asp、Cys、Gln、Glu、Gly、His、Met、Pro、Ser或Thr；e. When the substitution occurs at position 138, the substituting amino acid is Ala, Asn, Asp, Cys, Gln, Glu, Gly, His, Met, Pro, Ser or Thr; f.当取代发生在位点139时，取代氨基酸是Asn、Gln、Pro或Ser；和f. When the substitution occurs at position 139, the substituting amino acid is Asn, Gln, Pro or Ser; and g.当取代发生在位点141时，取代氨基酸是Asp或Glu；g. When the substitution occurs at position 141, the substituting amino acid is Asp or Glu; D.当取代发生在第四环区域中时，取代发生在位点167、169或171一个或多个上；其中D. When the substitution occurs in the fourth loop region, the substitution occurs at one or more of positions 167, 169, or 171; wherein a.当取代发生在位点167时，取代氨基酸是Asn、Asp、Gln、Glu、Pro或Ser；a. When the substitution occurs at position 167, the substituting amino acid is Asn, Asp, Gln, Glu, Pro or Ser; b当取代发生在位点169时，取代氨基酸是Asn、Asp、Gln、Glu、Gly或Ser；和b when the substitution occurs at position 169, the substituting amino acid is Asn, Asp, Gln, Glu, Gly or Ser; and c.当取代发生在位点171时，取代氨基酸是His、Ile、Leu、Met或Pro；c. When the substitution occurs at position 171, the substituting amino acid is His, Ile, Leu, Met or Pro; E.当取代发生在第五环区域中时，取代发生在位点193一个或多个上；其中E. When the substitution occurs in the fifth ring region, the substitution occurs at one or more of positions 193; wherein a.当取代发生在位点193时，取代氨基酸是Asn、Cys、Gln、His、Ile、Met、Thr或Tyr；a. When the substitution occurs at position 193, the substituting amino acid is Asn, Cys, Gln, His, Ile, Met, Thr or Tyr; F.当取代发生在第六环区域中时，取代发生在位点204、205、206、207、208、209、210、211、212、213、214、215、216、217、220、221、223或224的一个或多个上，其中F. When the substitution occurs in the sixth ring region, the substitution occurs at positions 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 220, 221, One or more of 223 or 224, where a.当取代发生在位点204时，取代氨基酸是Asn、Asp、Gln、Glu、Gly、His、Pro、Ser或Thr；a. When the substitution occurs at position 204, the substituting amino acid is Asn, Asp, Gln, Glu, Gly, His, Pro, Ser or Thr; b.当取代发生在位点205时，取代氨基酸是Asn、Asp、Gln、Glu、Gly或Ser；b. When the substitution occurs at position 205, the substituting amino acid is Asn, Asp, Gln, Glu, Gly or Ser; c.当取代发生在位点206时，取代氨基酸是Asn、Asp、Gln、Glu、Pro或Ser；c. When the substitution occurs at position 206, the substituting amino acid is Asn, Asp, Gln, Glu, Pro or Ser; d.当取代发生在位点207时，取代氨基酸是Asp或Glu；d. When the substitution occurs at position 207, the substituting amino acid is Asp or Glu; e.当取代发生在位点208时，取代氨基酸是Asp或Glu；e. When the substitution occurs at position 208, the substituting amino acid is Asp or Glu; f.当取代发生在位点209时，取代氨基酸是Ala、Asn、Asp、Cys、Gln、Glu、Gly、His、Leu、Met、Pro、Ser、Thr或Val；f. When the substitution occurs at position 209, the substituting amino acid is Ala, Asn, Asp, Cys, Gln, Glu, Gly, His, Leu, Met, Pro, Ser, Thr or Val; g.当取代发生在位点210时，取代氨基酸是Asp、His、Ile、Leu、Met或Pro；g. When the substitution occurs at position 210, the substituting amino acid is Asp, His, Ile, Leu, Met or Pro; h.当取代发生在位点211时，取代氨基酸是Asp或Glu；h. When the substitution occurs at position 211, the substituting amino acid is Asp or Glu; i.当取代发生在位点212时，取代氨基酸是Asn、Asp、Gln、Glu、Pro或Ser；i. When the substitution occurs at position 212, the substituting amino acid is Asn, Asp, Gln, Glu, Pro or Ser; j.当取代发生在位点213时，取代氨基酸是Asp、Glu、His、Ile、Leu、Met、Phe、Pro或Val；j. When the substitution occurs at position 213, the substituting amino acid is Asp, Glu, His, Ile, Leu, Met, Phe, Pro or Val; i.当取代发生在位点214时，取代氨基酸是Asn、Gln、Gly或Ser；i. When the substitution occurs at position 214, the substituting amino acid is Asn, Gln, Gly or Ser; j.当取代发生在位点215时，取代氨基酸是Asn、Asp、Gln、Glu、Pro或Ser；j. When the substitution occurs at position 215, the substituting amino acid is Asn, Asp, Gln, Glu, Pro or Ser; m.当取代发生在位点216时，取代氨基酸是Asp或Glu；m. When the substitution occurs at position 216, the substituting amino acid is Asp or Glu; n.当取代发生在位点217时，取代氨基酸是Asp、Glu或Pro；n. When the substitution occurs at position 217, the substituting amino acid is Asp, Glu or Pro; o.当取代发生在位点220时，取代氨基酸是Asp或Glu；o. When the substitution occurs at position 220, the substituting amino acid is Asp or Glu; p.当取代发生在位点221时，取代氨基酸是Ala、Asn、Asp、Cys、Gln、Glu、Gly、His、Ile、Met、Pro、Ser、Thr或Val；p. When the substitution occurs at position 221, the substituting amino acid is Ala, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Met, Pro, Ser, Thr or Val; q.当取代发生在位点222时，取代氨基酸是Asp或Glu；q. When the substitution occurs at position 222, the substituting amino acid is Asp or Glu; r.当取代发生在位点223时，取代氨基酸是Asn、Asp、Gln、Glu、Pro或Ser；r. When the substitution occurs at position 223, the substituting amino acid is Asn, Asp, Gln, Glu, Pro or Ser; s.当取代发生在位点224时，取代氨基酸是Asn、Asp、Gln、Glu、Pro或Ser；s. When the substitution occurs at position 224, the substituting amino acid is Asn, Asp, Gln, Glu, Pro or Ser; 从而，与野生型热酶相比较，热酶变异体对不溶解底物具有降低的吸附作用和增加的水解作用。Thus, thermozyme variants have reduced adsorption and increased hydrolysis of insoluble substrates compared to wild-type thermozymes. 2.权利要求1的热酶变异体，其中一个或多个取代基发生在第一环区域。2. The thermozyme variant of claim 1, wherein one or more substituents occur in the first loop region. 3.权利要求1的热酶变异体，其中一个或多个取代基发生在第二环区域。3. The thermozyme variant of claim 1, wherein one or more substituents occur in the second loop region. 4.权利要求1的热酶变异体，其中一个或多个取代基发生在第三环区域。4. The thermozyme variant of claim 1, wherein one or more substituents occur in the third loop region. 5.权利要求1的热酶变异体，其中一个或多个取代基发生在第四环区域。5. The thermozyme variant of claim 1, wherein one or more substituents occur in the fourth loop region. 6.权利要求1的热酶变异体，其中一个或多个取代基发生在第五环区域。6. The thermozyme variant of claim 1, wherein one or more substituents occur in the fifth loop region. 7.权利要求1的热酶变异体，其中一个或多个取代基发生在第六环区域。7. The thermozyme variant of claim 1, wherein one or more substituents occur in the sixth loop region. 8.一种选自硬表面洗涤组合物、餐具洗涤组合物、口腔洗涤组合物、假牙洗涤组合物、接触透镜洗涤组合物和织物洗涤组合物的洗涤组合物，其特征在于其中洗涤组合物含有权利要求1-7的任何一项的热酶变异体和洗涤组合物载体；洗涤组合物优选是硬表面洗涤组合物或洗涤组合物是织物洗涤组合物；组合物优选含有按组合物重量计至少约5％的表面活性剂和至少约5％助剂；组合物还优选含有选自溶剂、缓冲剂、酶、污垢解脱剂、粘土去污剂、分散剂、增白剂、泡沫抑制剂、织物柔软剂、增泡剂、酶稳定剂、漂白剂、染料、香料和它们的混合物的洗涤组合物材料。8. A cleaning composition selected from the group consisting of hard surface cleaning compositions, dishwashing compositions, oral cavity cleaning compositions, denture cleaning compositions, contact lens cleaning compositions and fabric cleaning compositions, characterized in that the cleaning composition contains The thermal enzyme variant of any one of claims 1-7 and the carrier of the washing composition; The washing composition is preferably a hard surface washing composition or the washing composition is a fabric washing composition; The composition preferably contains at least About 5% surfactant and at least about 5% adjuvants; the composition also preferably contains solvents, buffers, enzymes, soil release agents, clay soil removers, dispersants, brighteners, foam suppressors, fabric Detergent composition materials of softeners, suds boosters, enzyme stabilizers, bleaches, dyes, perfumes and mixtures thereof. 9.编码权利要求1-7的任何一项的热酶变异体的DNA序列。9. A DNA sequence encoding a thermozyme variant according to any one of claims 1-7.
CN96193608A 1995-03-09 1996-03-06 Thermitase variants having decreased adsorption and increased hydrolysis Pending CN1183118A (en)

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US7319112B2 (en) 2000-07-14 2008-01-15 The Procter & Gamble Co. Non-halogenated antibacterial agents and processes for making same
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