5b5t: Difference between revisions
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==Crystal Structure of Escherichia coli Gamma-Glutamyltranspeptidase in Complex with peptidyl phosphonate inhibitor 1b== | |||
<StructureSection load='5b5t' size='340' side='right'caption='[[5b5t]], [[Resolution|resolution]] 1.70Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[5b5t]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli_K-12 Escherichia coli K-12]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5B5T OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5B5T FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.7Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6FY:(2~{S})-2-AZANYL-4-[(2~{R})-1-(2-HYDROXY-2-OXOETHYLAMINO)-1-OXIDANYLIDENE-BUTAN-2-YL]OXYPHOSPHONOYL-BUTANOIC+ACID'>6FY</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5b5t FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5b5t OCA], [https://pdbe.org/5b5t PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5b5t RCSB], [https://www.ebi.ac.uk/pdbsum/5b5t PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5b5t ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/GGT_ECOLI GGT_ECOLI] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
gamma-Glutamyl transpeptidase (GGT, EC 2.3.2.2) that catalyzes the hydrolysis and transpeptidation of glutathione and its S-conjugates is involved in a number of physiological and pathological processes through glutathione metabolism and is an attractive pharmaceutical target. We report here the evaluation of a phosphonate-based irreversible inhibitor, 2-amino-4-{[3-(carboxymethyl)phenoxy](methoyl)phosphoryl}butanoic acid (GGsTop) and its analogues as a mechanism-based inhibitor of human GGT. GGsTop is a stable compound, but inactivated the human enzyme significantly faster than the other phosphonates, and importantly did not inhibit a glutamine amidotransferase. The structure-activity relationships, X-ray crystallography with Escherichia coli GGT, sequence alignment and site-directed mutagenesis of human GGT revealed a critical electrostatic interaction between the terminal carboxylate of GGsTop and the active-site residue Lys562 of human GGT for potent inhibition. GGsTop showed no cytotoxicity toward human fibroblasts and hepatic stellate cells up to 1mM. GGsTop serves as a non-toxic, selective and highly potent irreversible GGT inhibitor that could be used for various in vivo as well as in vitro biochemical studies. | |||
Phosphonate-based irreversible inhibitors of human gamma-glutamyl transpeptidase (GGT). GGsTop is a non-toxic and highly selective inhibitor with critical electrostatic interaction with an active-site residue Lys562 for enhanced inhibitory activity.,Kamiyama A, Nakajima M, Han L, Wada K, Mizutani M, Tabuchi Y, Kojima-Yuasa A, Matsui-Yuasa I, Suzuki H, Fukuyama K, Watanabe B, Hiratake J Bioorg Med Chem. 2016 Aug 31. pii: S0968-0896(16)30667-8. doi:, 10.1016/j.bmc.2016.08.050. PMID:27622749<ref>PMID:27622749</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 5b5t" style="background-color:#fffaf0;"></div> | ||
[[Category: | == References == | ||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Escherichia coli K-12]] | |||
[[Category: Large Structures]] | |||
[[Category: Fukuyama K]] | |||
[[Category: Wada K]] | |||
Latest revision as of 16:00, 8 November 2023
Crystal Structure of Escherichia coli Gamma-Glutamyltranspeptidase in Complex with peptidyl phosphonate inhibitor 1b
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