Papers by George Phillips
Journal of Computational Biology, Jun 1, 2003
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Proteins, Sep 13, 2011
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ACS Sustainable Chemistry & Engineering, Jan 23, 2020
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We report the identification of the ter gene cluster responsible for the formation of the p-terph... more We report the identification of the ter gene cluster responsible for the formation of the p-terphenyl derivatives terfestatins B and C and echoside B from the Appalachian Streptomyces strain RM-5-8. We characterize the function of TerB/C, catalysts that work together as a dual enzyme system in the biosynthesis of natural terphenyls. TerB acts as a reductase and TerC as a dehydratase to enable the conversion of polyporic acid to a terphenyl triol intermediate. X-ray crystallography of the apo and substrate-bound forms for both enzymes provides additional mechanistic insights. Validation of the TerC structural model via mutagenesis highlights a critical role of arginine 143 and aspartate 173 in catalysis. Cumulatively, this work highlights a set of enzymes acting in harmony to control and direct reactive intermediates and advances fundamental understanding of the previously unresolved early steps in terphenyl biosynthesis.
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Proteins: Structure, Function, and Bioinformatics, 2019
The functional and biological significance of selected CASP13 targets are described by the author... more The functional and biological significance of selected CASP13 targets are described by the authors of the structures. The structural biologists discuss the most interesting structural features of the target proteins and assess whether these features were correctly reproduced in the predictions submitted to the CASP13 experiment.
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Nature chemical biology, 2018
Acyl-coenzyme A (CoA) ligases catalyze the activation of carboxylic acids via a two-step reaction... more Acyl-coenzyme A (CoA) ligases catalyze the activation of carboxylic acids via a two-step reaction of adenylation followed by thioesterification. Here, we report the discovery of a non-adenylating acyl-CoA ligase PtmA2 and the functional separation of an acyl-CoA ligase reaction. Both PtmA1 and PtmA2, two acyl-CoA ligases from the biosynthetic pathway of platensimycin and platencin, are necessary for the two steps of CoA activation. Gene inactivation of ptmA1 and ptmA2 resulted in the accumulation of free acid and adenylate intermediates, respectively. Enzymatic and structural characterization of PtmA2 confirmed its ability to only catalyze thioesterification. Structural characterization of PtmA2 revealed it binds both free acid and adenylate substrates and undergoes the established mechanism of domain alternation. Finally, site-directed mutagenesis restored both the adenylation and complete CoA activation reactions. This study challenges the currently accepted paradigm of adenylatin...
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Proteins, 2004
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Proteins: Structure, Function, and Bioinformatics, 2013
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Proteins: Structure, Function, and Bioinformatics, 2011
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Proteins: Structure, Function, and Bioinformatics, 2011
Mitomycins are quinone‐containing antibiotics, widely used as antitumor drugs in chemotherapy. Mi... more Mitomycins are quinone‐containing antibiotics, widely used as antitumor drugs in chemotherapy. Mitomycin‐7‐O‐methyltransferase (MmcR), a key tailoring enzyme involved in the biosynthesis of mitomycin in Streptomyces lavendulae, catalyzes the 7‐O‐methylation of both C9β‐ and C9α‐configured 7‐hydroxymitomycins. We have determined the crystal structures of the MmcR–S‐adenosylhomocysteine (SAH) binary complex and MmcR–SAH–mitomycin A (MMA) ternary complex at resolutions of 1.9and 2.3 Å, respectively. The study revealed MmcR to adopt a common S‐adenosyl‐L‐methionine‐dependent O‐methyltransferase fold and the presence of a structurally conserved active site general acid–base pair is consistent with a proton‐assisted methyltransfer common to most methyltransferases. Given the importance of C7 alkylation to modulate mitomycin redox potential, this study may also present a template toward the future engineering of catalysts to generate uniquely bioactive mitomycins. Proteins 2011. © 2011 Wil...
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Proteins: Structure, Function, and Bioinformatics, 2010
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Proteins: Structure, Function, and Bioinformatics, 2009
Although bacterial iterative Type I polyketide synthases are now known to participate in the bios... more Although bacterial iterative Type I polyketide synthases are now known to participate in the biosynthesis of a small set of diverse natural products, the subsequent downstream modification of the resulting polyketide products remains poorly understood. Toward this goal, we report the X‐ray structure determination at 2.5 Å resolution and preliminary characterization of the putative orsellenic acid P450 oxidase (CalO2) involved in calicheamicin biosynthesis. These studies represent the first crystal structure for a P450 involved in modifying a bacterial iterative Type I polyketide product and suggest the CalO2‐catalyzed step may occur after CalO3‐catalyzed iodination and may also require a coenzyme A‐ (CoA) or acyl carrier protein‐ (ACP) bound substrate. Docking studies also reveal a putative docking site within CalO2 for the CLM orsellinic acid synthase (CalO5) ACP domain which involves a well‐ordered helix along the CalO2 active site cavity that is unique compared with other P450 st...
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Journal of Structural and Functional Genomics, 2010
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Journal of Molecular Biology, 2008
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Journal of Molecular Biology, 2010
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Journal of Molecular Biology, 2007
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Papers by George Phillips