1va6

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{{STRUCTURE_1va6| PDB=1va6 | SCENE= }}
{{STRUCTURE_1va6| PDB=1va6 | SCENE= }}
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'''Crystal structure of Gamma-glutamylcysteine synthetase from Escherichia Coli B complexed with Transition-state analogue'''
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===Crystal structure of Gamma-glutamylcysteine synthetase from Escherichia Coli B complexed with Transition-state analogue===
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==Overview==
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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.
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The line below this paragraph, {{ABSTRACT_PUBMED_15477603}}, adds the Publication Abstract to the page
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(as it appears on PubMed at http://www.pubmed.gov), where 15477603 is the PubMed ID number.
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{{ABSTRACT_PUBMED_15477603}}
==About this Structure==
==About this Structure==
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==Reference==
==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:[http://www.ncbi.nlm.nih.gov/pubmed/15477603 15477603]
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:[http://www.ncbi.nlm.nih.gov/pubmed/15477603 15477603]
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Escherichia coli B gamma-glutamylcysteine synthetase: modification, purification, crystallization and preliminary crystallographic analysis., Hibi T, Hisada H, Nakatsu T, Kato H, Oda J, Acta Crystallogr D Biol Crystallogr. 2002 Feb;58(Pt 2):316-8. Epub 2002, Jan 24. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/11807262 11807262]
[[Category: Escherichia coli]]
[[Category: Escherichia coli]]
[[Category: Glutamate--cysteine ligase]]
[[Category: Glutamate--cysteine ligase]]
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[[Category: Peptide synthesis]]
[[Category: Peptide synthesis]]
[[Category: Transition state analogue]]
[[Category: Transition state analogue]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 13:55:23 2008''

Revision as of 10:55, 28 July 2008

Image:1va6.png

Template:STRUCTURE 1va6

Crystal structure of Gamma-glutamylcysteine synthetase from Escherichia Coli B complexed with Transition-state analogue

Template:ABSTRACT PUBMED 15477603

About this Structure

1VA6 is a Single protein structure of sequence from Escherichia coli. 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

Escherichia coli B gamma-glutamylcysteine synthetase: modification, purification, crystallization and preliminary crystallographic analysis., Hibi T, Hisada H, Nakatsu T, Kato H, Oda J, Acta Crystallogr D Biol Crystallogr. 2002 Feb;58(Pt 2):316-8. Epub 2002, Jan 24. PMID:11807262

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