1v4g
From Proteopedia
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Crystal Structure of gamma-Glutamylcysteine Synthetase from Escherichia coli B
Overview
Gamma-glutamylcysteine synthetase (gammaGCS), a rate-limiting enzyme in, glutathione biosynthesis, plays a central role in glutathione homeostasis, and is a target for development of potential therapeutic agents against, parasites and cancer. We have determined the crystal structures of, Escherichia coli gammaGCS unliganded and complexed with a, sulfoximine-based transition-state analog inhibitor at resolutions of 2.5, and 2.1 A, respectively. In the crystal structure of the complex, the, bound inhibitor is phosphorylated at the sulfoximido nitrogen and is, coordinated to three Mg2+ ions. The cysteine-binding site was identified;, it is formed inductively at the transition state. In the unliganded, structure, an open space exists around the representative cysteine-binding, site and is probably responsible for the competitive binding of, glutathione. Upon inhibitor binding, the side chains of Tyr-241 and, Tyr-300 turn, forming a hydrogen-bonding triad with the carboxyl group of, the inhibitor's cysteine moiety, allowing this moiety to fit tightly into, the cysteine-binding site with concomitant accommodation of its side chain, into a shallow pocket. This movement is caused by a conformational change, of a switch loop (residues 240-249). Based on this crystal structure, the, cysteine-binding sites of mammalian and parasitic gammaGCSs were predicted, by multiple sequence alignment, although no significant sequence identity, exists between the E. coli gammaGCS and its eukaryotic homologues. The, identification of this cysteine-binding site provides important, information for the rational design of novel gammaGCS inhibitors.
About this Structure
1V4G is a Single protein structure of sequence from Escherichia coli. Active as Glutamate--cysteine ligase, with EC number 6.3.2.2 Full crystallographic information is available from OCA.
Reference
Crystal structure of gamma-glutamylcysteine synthetase: insights into the mechanism of catalysis by a key enzyme for glutathione homeostasis., Hibi T, Nii H, Nakatsu T, Kimura A, Kato H, Hiratake J, Oda J, Proc Natl Acad Sci U S A. 2004 Oct 19;101(42):15052-7. Epub 2004 Oct 11. PMID:15477603
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