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Denis Moras

    Denis Moras

    The plasma protein inhibitor anti thrombin III in its native form has been crystallized using standard techniques.The crystals diffract to about and belong to space group P41212 with cell parameters:a = b = 90.6<, c = 380.7<.The... more
    The plasma protein inhibitor anti thrombin III in its native form has been crystallized using standard techniques.The crystals diffract to about and belong to space group P41212 with cell parameters:a = b = 90.6<, c = 380.7<.The asymmetric unit contains three molecules of anti thrombin III.The self rotation function computed with the native data set indicates the presence of a non crystallographic three fold axis. Cross rotation function calculations using themodel of the cleaved α1,-antitrypsin (H. Loebermann at.,J. Mol. Biol.(1985) 177, 531) suggests tertiary structuresimilarities between the two plasma proteins.This is in agreement with the already described primary sequence homology of these glycoproteins but at variance with the model of active α1-anti trypsin inferred from the previous studies on the cleaved molecule.The technical assistance of M. Maman is deeply appreciated.
    Research Interests:
    Hepatocyte Nuclear Factor 4 (HNF4) is a transcription factor (TF) belonging to the nuclear receptor (NR) family that is expressed in liver, kidney, intestine and pancreas. It is a master regulator of liver-specific gene expression, in... more
    Hepatocyte Nuclear Factor 4 (HNF4) is a transcription factor (TF) belonging to the nuclear receptor (NR) family that is expressed in liver, kidney, intestine and pancreas. It is a master regulator of liver-specific gene expression, in particular those genes involved in lipid transport and glucose metabolism and is crucial for the cellular differentiation during development. Dysregulation of HNF4 is linked to human diseases, such as type I diabetes (MODY1) and hemophilia. Here, we review the structures of the isolated HNF4 DNA binding domain (DBD) and ligand binding domain (LBD) and that of the multidomain receptor and compare them with the structures of other NRs. We will further discuss the biology of the HNF4α receptors from a structural perspective, in particular the effect of pathological mutations and of functionally critical post-translational modifications on the structure-function of the receptor.
    Hepatocyte Nuclear Factor 4 (HNF4) is a transcription factor (TF) belonging to the nuclear receptor (NR) family that is expressed in liver, kidney, intestine and pancreas. It is a master regulator of liver-specific gene expression, in... more
    Hepatocyte Nuclear Factor 4 (HNF4) is a transcription factor (TF) belonging to the nuclear receptor (NR) family that is expressed in liver, kidney, intestine and pancreas. It is a master regulator of liver-specific gene expression, in particular those genes involved in lipid transport and glucose metabolism and is crucial for the cellular differentiation during development. Dysregulation of HNF4 is linked to human diseases, such as type I diabetes (MODY1) and hemophilia. Here, we review the structures of the isolated HNF4 DNA binding domain (DBD) and ligand binding domain (LBD) and that of the multidomain receptor and compare them with the structures of other NRs. We will further discuss the biology of the HNF4α receptors from a structural perspective, in particular the effect of pathological mutations and of functionally critical post-translational modifications on the structure-function of the receptor.
    Aminoacyl-tRNA synthetases (aaRS) constitute a family of enzymes that catalyze the specific attachment of one amino acid (aa) to its cognate tRNA in what is a key step in the translation of the genetic information during protein... more
    Aminoacyl-tRNA synthetases (aaRS) constitute a family of enzymes that catalyze the specific attachment of one amino acid (aa) to its cognate tRNA in what is a key step in the translation of the genetic information during protein biosynthesis. This enzymatic reaction requires ATP and can be decomposed in two steps: $$\begin{gathered} \operatorname{aa} + ATP \to aa - AMP + PPi \hfill \\ \operatorname{aa} - AMP + tRNA \to aa - tRNA + AMP \hfill \\ \end{gathered} $$
    Hepatocyte Nuclear Factor 4 (HNF4) is a transcription factor (TF) belonging to the nuclear receptor (NR) family that is expressed in liver, kidney, intestine and pancreas. It is a master regulator of liver-specific gene expression, in... more
    Hepatocyte Nuclear Factor 4 (HNF4) is a transcription factor (TF) belonging to the nuclear receptor (NR) family that is expressed in liver, kidney, intestine and pancreas. It is a master regulator of liver-specific gene expression, in particular those genes involved in lipid transport and glucose metabolism and is crucial for the cellular differentiation during development. Dysregulation of HNF4 is linked to human diseases, such as type I diabetes (MODY1) and hemophilia. Here, we review the structures of the isolated HNF4 DNA binding domain (DBD) and ligand binding domain (LBD) and that of the multidomain receptor and compare them with the structures of other NRs. We will further discuss the biology of the HNF4α receptors from a structural perspective, in particular the effect of pathological mutations and of functionally critical post-translational modifications on the structure-function of the receptor.
    Aminoacyl-tRNA synthetases (aaRS) constitute a family of enzymes that catalyze the specific attachment of one amino acid (aa) to its cognate tRNA in what is a key step in the translation of the genetic information during protein... more
    Aminoacyl-tRNA synthetases (aaRS) constitute a family of enzymes that catalyze the specific attachment of one amino acid (aa) to its cognate tRNA in what is a key step in the translation of the genetic information during protein biosynthesis. This enzymatic reaction requires ATP and can be decomposed in two steps: $$\begin{gathered} \operatorname{aa} + ATP \to aa - AMP + PPi \hfill \\ \operatorname{aa} - AMP + tRNA \to aa - tRNA + AMP \hfill \\ \end{gathered} $$
    Aminoacyl-tRNA synthetases (aaRS) constitute a family of enzymes that catalyze the specific attachment of one amino acid (aa) to its cognate tRNA in what is a key step in the translation of the genetic information during protein... more
    Aminoacyl-tRNA synthetases (aaRS) constitute a family of enzymes that catalyze the specific attachment of one amino acid (aa) to its cognate tRNA in what is a key step in the translation of the genetic information during protein biosynthesis. This enzymatic reaction requires ATP and can be decomposed in two steps: $$\begin{gathered} \operatorname{aa} + ATP \to aa - AMP + PPi \hfill \\ \operatorname{aa} - AMP + tRNA \to aa - tRNA + AMP \hfill \\ \end{gathered} $$
    The partition of aminoacyl-tRNA synthetases (aaRSs) into two classes of equal size and the correlated amino acid distribution is a puzzling still unexplained observation. We propose that the time scale of the amino-acid synthesis, assumed... more
    The partition of aminoacyl-tRNA synthetases (aaRSs) into two classes of equal size and the correlated amino acid distribution is a puzzling still unexplained observation. We propose that the time scale of the amino-acid synthesis, assumed to be proportional to the number of reaction steps (NE) involved in the biosynthesis pathway, is one of the parameters that controlled the timescale of aaRSs appearance. Because all pathways are branched at fructose-6-phosphate on the metabolic pathway, this product is defined as the common origin for the NE comparison. For each amino-acid, the NE value, counted from the origin to the final product, provides a timescale for the pathways to be established. An archeological approach based on NE reveals that aaRSs of the two classes are generated in pair along this timescale. The results support the coevolution theory for the origin of the genetic code with an earlier appearance of class II aaRSs.
    Aminoacyl-tRNA synthetases play a central role in maintaining accuracy during the translation of the genetic code. To achieve this challenging task they have to discriminate against amino acids that are very closely related not only in... more
    Aminoacyl-tRNA synthetases play a central role in maintaining accuracy during the translation of the genetic code. To achieve this challenging task they have to discriminate against amino acids that are very closely related not only in structure but also in chemical nature. A 'double-sieve' editing model was proposed in the late seventies to explain how two closely related amino acids may be discriminated. However, a clear understanding of this mechanism required structural information on synthetases that are faced with such a problem of amino acid discrimination. The first structural basis for the editing model came recently from the crystal structure of isoleucyl-tRNA synthetase, a class I synthetase, which has to discriminate against valine. The structure showed the presence of two catalytic sites in the same enzyme, one for activation, a coarse sieve which binds both isoleucine and valine, and another for editing, a fine sieve which binds only valine and rejects isoleuci...
    The partition of aminoacyl-tRNA synthetases (aaRSs) into two classes of equal size and the correlated amino acid distribution is a puzzling still unexplained observation. We propose that the time scale of the amino-acid synthesis, assumed... more
    The partition of aminoacyl-tRNA synthetases (aaRSs) into two classes of equal size and the correlated amino acid distribution is a puzzling still unexplained observation. We propose that the time scale of the amino-acid synthesis, assumed to be proportional to the number of reaction steps (NE) involved in the biosynthesis pathway, is one of the parameters that controlled the timescale of aaRSs appearance. Because all pathways are branched at fructose-6-phosphate on the metabolic pathway, this product is defined as the common origin for the NE comparison. For each amino-acid, the NE value, counted from the origin to the final product, provides a timescale for the pathways to be established. An archeological approach based on NE reveals that aaRSs of the two classes are generated in pair along this timescale. The results support the coevolution theory for the origin of the genetic code with an earlier appearance of class II aaRSs.
    Aminoacyl-tRNA synthetases play a central role in maintaining accuracy during the translation of the genetic code. To achieve this challenging task they have to discriminate against amino acids that are very closely related not only in... more
    Aminoacyl-tRNA synthetases play a central role in maintaining accuracy during the translation of the genetic code. To achieve this challenging task they have to discriminate against amino acids that are very closely related not only in structure but also in chemical nature. A 'double-sieve' editing model was proposed in the late seventies to explain how two closely related amino acids may be discriminated. However, a clear understanding of this mechanism required structural information on synthetases that are faced with such a problem of amino acid discrimination. The first structural basis for the editing model came recently from the crystal structure of isoleucyl-tRNA synthetase, a class I synthetase, which has to discriminate against valine. The structure showed the presence of two catalytic sites in the same enzyme, one for activation, a coarse sieve which binds both isoleucine and valine, and another for editing, a fine sieve which binds only valine and rejects isoleuci...
    The partition of aminoacyl-tRNA synthetases (aaRSs) into two classes of equal size and the correlated amino acid distribution is a puzzling still unexplained observation. We propose that the time scale of the amino-acid synthesis, assumed... more
    The partition of aminoacyl-tRNA synthetases (aaRSs) into two classes of equal size and the correlated amino acid distribution is a puzzling still unexplained observation. We propose that the time scale of the amino-acid synthesis, assumed to be proportional to the number of reaction steps (NE) involved in the biosynthesis pathway, is one of the parameters that controlled the timescale of aaRSs appearance. Because all pathways are branched at fructose-6-phosphate on the metabolic pathway, this product is defined as the common origin for the NE comparison. For each amino-acid, the NE value, counted from the origin to the final product, provides a timescale for the pathways to be established. An archeological approach based on NE reveals that aaRSs of the two classes are generated in pair along this timescale. The results support the coevolution theory for the origin of the genetic code with an earlier appearance of class II aaRSs.
    Aminoacyl-tRNA synthetases play a central role in maintaining accuracy during the translation of the genetic code. To achieve this challenging task they have to discriminate against amino acids that are very closely related not only in... more
    Aminoacyl-tRNA synthetases play a central role in maintaining accuracy during the translation of the genetic code. To achieve this challenging task they have to discriminate against amino acids that are very closely related not only in structure but also in chemical nature. A 'double-sieve' editing model was proposed in the late seventies to explain how two closely related amino acids may be discriminated. However, a clear understanding of this mechanism required structural information on synthetases that are faced with such a problem of amino acid discrimination. The first structural basis for the editing model came recently from the crystal structure of isoleucyl-tRNA synthetase, a class I synthetase, which has to discriminate against valine. The structure showed the presence of two catalytic sites in the same enzyme, one for activation, a coarse sieve which binds both isoleucine and valine, and another for editing, a fine sieve which binds only valine and rejects isoleuci...
    R,3R,11R,12R)-l,4,7,10,13,16-Hexaoxa- cyclooctadecane-2,3,11,12-tetracarboxylic acid mono- hydrazinium monotetramethylammonium salt mono- + + 2-- hydrate, CaHI2N.HsN 2.C16HEEOI4.H20, Mr= 563.6, monoclinic, P2,, a = 12.075 (I), b = 14.436... more
    R,3R,11R,12R)-l,4,7,10,13,16-Hexaoxa- cyclooctadecane-2,3,11,12-tetracarboxylic acid mono- hydrazinium monotetramethylammonium salt mono- + + 2-- hydrate, CaHI2N.HsN 2.C16HEEOI4.H20, Mr= 563.6, monoclinic, P2,, a = 12.075 (I), b = 14.436 (4), c = 8.018.(1)A, fl= 95.45 (1) °, U= 1391 ./k 3, Z= 2, D x = 1.35 g cm -3, 2 = 1.5418/~, g(Cu Kct) = 9.5 cm -1, F(000) = 604, T-- 292 K, R = 0.079 and wR -- 0.118 for 2155 observed data. The macrocyclic dianionic ligand is in a relaxed conformation, with a rectangular array of ether O atoms in the mean plane of the ring, the two other O atoms being out of the plane in the direction towards the complexed cation. The hydrazinium monocation is anchored to the ligand by three N-H...O hydrogen bonds. Introduction. The conjunction of a macrocyclic poly- ether core and anionic groups surrounding this molecular cavity makes the tetracarboxy-18-crown-6 ligand (Behr, Girodeau, Hayward, Lehn & Sauvage, 1980) a very powerful complexing agent for cations (Lehn, 1978; Behr, Lehn & Vierling, 1982). With the idea of taking advantage of this property to stabilize unusual cations (Behr, Dumas & Moras, 1982), we crystallized an adduct with hydrazine from water at pH -- 4. We hoped that, although partly protonated, the ligand would still be a strong enough complexing agent to stabilize the H3~-NH 3 dication which normally exists only in strong acid. Attempts to characterize this complex by indirect physical techniques (NMR, pH-- metric titration) were unsuccessful since the sequential protonation of a tetracarboxylate ligand/hydrazine mixture leads to ambiguous interpretations of whether protonation occurs on a carboxylate or an amino group. We therefore undertook the X-ray analysis of a complex crystallized in medium acidic conditions. Experimental. A single crystal with approximate dimen- sions 0.34 × 0.29 x 0.23 mm was sealed in a Linde- mann-glass capillary and optically aligned on a Nonius CAD-4 diffractometer. Preliminary study and data 0108-2701/87/112134-04501.50
    R,3R,11R,12R)-l,4,7,10,13,16-Hexaoxa- cyclooctadecane-2,3,11,12-tetracarboxylic acid mono- hydrazinium monotetramethylammonium salt mono- + + 2-- hydrate, CaHI2N.HsN 2.C16HEEOI4.H20, Mr= 563.6, monoclinic, P2,, a = 12.075 (I), b = 14.436... more
    R,3R,11R,12R)-l,4,7,10,13,16-Hexaoxa- cyclooctadecane-2,3,11,12-tetracarboxylic acid mono- hydrazinium monotetramethylammonium salt mono- + + 2-- hydrate, CaHI2N.HsN 2.C16HEEOI4.H20, Mr= 563.6, monoclinic, P2,, a = 12.075 (I), b = 14.436 (4), c = 8.018.(1)A, fl= 95.45 (1) °, U= 1391 ./k 3, Z= 2, D x = 1.35 g cm -3, 2 = 1.5418/~, g(Cu Kct) = 9.5 cm -1, F(000) = 604, T-- 292 K, R = 0.079 and wR -- 0.118 for 2155 observed data. The macrocyclic dianionic ligand is in a relaxed conformation, with a rectangular array of ether O atoms in the mean plane of the ring, the two other O atoms being out of the plane in the direction towards the complexed cation. The hydrazinium monocation is anchored to the ligand by three N-H...O hydrogen bonds. Introduction. The conjunction of a macrocyclic poly- ether core and anionic groups surrounding this molecular cavity makes the tetracarboxy-18-crown-6 ligand (Behr, Girodeau, Hayward, Lehn & Sauvage, 1980) a very powerful complexing agent for cations (Lehn, 1978; Behr, Lehn & Vierling, 1982). With the idea of taking advantage of this property to stabilize unusual cations (Behr, Dumas & Moras, 1982), we crystallized an adduct with hydrazine from water at pH -- 4. We hoped that, although partly protonated, the ligand would still be a strong enough complexing agent to stabilize the H3~-NH 3 dication which normally exists only in strong acid. Attempts to characterize this complex by indirect physical techniques (NMR, pH-- metric titration) were unsuccessful since the sequential protonation of a tetracarboxylate ligand/hydrazine mixture leads to ambiguous interpretations of whether protonation occurs on a carboxylate or an amino group. We therefore undertook the X-ray analysis of a complex crystallized in medium acidic conditions. Experimental. A single crystal with approximate dimen- sions 0.34 × 0.29 x 0.23 mm was sealed in a Linde- mann-glass capillary and optically aligned on a Nonius CAD-4 diffractometer. Preliminary study and data 0108-2701/87/112134-04501.50
    R,3R,11R,12R)-l,4,7,10,13,16-Hexaoxa- cyclooctadecane-2,3,11,12-tetracarboxylic acid mono- hydrazinium monotetramethylammonium salt mono- + + 2-- hydrate, CaHI2N.HsN 2.C16HEEOI4.H20, Mr= 563.6, monoclinic, P2,, a = 12.075 (I), b = 14.436... more
    R,3R,11R,12R)-l,4,7,10,13,16-Hexaoxa- cyclooctadecane-2,3,11,12-tetracarboxylic acid mono- hydrazinium monotetramethylammonium salt mono- + + 2-- hydrate, CaHI2N.HsN 2.C16HEEOI4.H20, Mr= 563.6, monoclinic, P2,, a = 12.075 (I), b = 14.436 (4), c = 8.018.(1)A, fl= 95.45 (1) °, U= 1391 ./k 3, Z= 2, D x = 1.35 g cm -3, 2 = 1.5418/~, g(Cu Kct) = 9.5 cm -1, F(000) = 604, T-- 292 K, R = 0.079 and wR -- 0.118 for 2155 observed data. The macrocyclic dianionic ligand is in a relaxed conformation, with a rectangular array of ether O atoms in the mean plane of the ring, the two other O atoms being out of the plane in the direction towards the complexed cation. The hydrazinium monocation is anchored to the ligand by three N-H...O hydrogen bonds. Introduction. The conjunction of a macrocyclic poly- ether core and anionic groups surrounding this molecular cavity makes the tetracarboxy-18-crown-6 ligand (Behr, Girodeau, Hayward, Lehn & Sauvage, 1980) a very powerful complexing agent for cations (Lehn, 1978; Behr, Lehn & Vierling, 1982). With the idea of taking advantage of this property to stabilize unusual cations (Behr, Dumas & Moras, 1982), we crystallized an adduct with hydrazine from water at pH -- 4. We hoped that, although partly protonated, the ligand would still be a strong enough complexing agent to stabilize the H3~-NH 3 dication which normally exists only in strong acid. Attempts to characterize this complex by indirect physical techniques (NMR, pH-- metric titration) were unsuccessful since the sequential protonation of a tetracarboxylate ligand/hydrazine mixture leads to ambiguous interpretations of whether protonation occurs on a carboxylate or an amino group. We therefore undertook the X-ray analysis of a complex crystallized in medium acidic conditions. Experimental. A single crystal with approximate dimen- sions 0.34 × 0.29 x 0.23 mm was sealed in a Linde- mann-glass capillary and optically aligned on a Nonius CAD-4 diffractometer. Preliminary study and data 0108-2701/87/112134-04501.50

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