1i41
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(New page: 200px<br /><applet load="1i41" size="450" color="white" frame="true" align="right" spinBox="true" caption="1i41, resolution 3.2Å" /> '''CYSTATHIONINE GAMMA-S...)
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Revision as of 01:26, 25 November 2007
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CYSTATHIONINE GAMMA-SYNTHASE IN COMPLEX WITH THE INHIBITOR APPA
Overview
Cystathionine gamma-synthase catalyzes the committed step of methionine, biosynthesis. This pathway is unique to microorganisms and plants, rendering the enzyme an attractive target for the development of, antimicrobials and herbicides. We solved the crystal structures of, complexes of cystathionine gamma-synthase (CGS) from Nicotiana tabacum, with inhibitors of different compound classes. The complex with the, substrate analog dl-E-2-amino-5-phosphono-3-pentenoic acid verifies the, carboxylate-binding function of Arg423 and identifies the, phosphate-binding pocket of the active site. The structure shows the, function of Lys165 in specificity determination and suggests a role for, the flexible side-chain of Tyr163 in catalysis. The importance of, hydrophobic interactions for binding to the active-site center is, highlighted by the complex with 3-(phosphonomethyl)pyridine-2-carboxylic, acid. The low affinity of this compound is due to the non-optimal, arrangement of the functional groups binding to the phosphate and, carboxylate-recognition site, respectively. The newly identified inhibitor, 5-carboxymethylthio-3-(3'-chlorophenyl)-1,2,4-oxadiazol, in contrast, shows the highest affinity to CGS reported so far. This affinity is due to, binding to an additional active-site pocket not used by the physiological, substrates. The inhibitor binds to the carboxylate-recognition site, and, its tightly bent conformation enables it to occupy the novel binding, pocket between Arg423 and Ser388. The described structures suggest, improvements for known inhibitors and give guidelines for the development, of new lead compounds.
About this Structure
1I41 is a Single protein structure of sequence from Nicotiana tabacum with HEN as ligand. Active as Cystathionine gamma-synthase, with EC number 2.5.1.48 Full crystallographic information is available from OCA.
Reference
Crystal structures of cystathionine gamma-synthase inhibitor complexes rationalize the increased affinity of a novel inhibitor., Steegborn C, Laber B, Messerschmidt A, Huber R, Clausen T, J Mol Biol. 2001 Aug 24;311(4):789-801. PMID:11518531
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