3zei: Difference between revisions
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==Structure of the Mycobacterium tuberculosis O-Acetylserine Sulfhydrylase (OASS) CysK1 in complex with a small molecule inhibitor== | |||
<StructureSection load='3zei' size='340' side='right' caption='[[3zei]], [[Resolution|resolution]] 2.00Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[3zei]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3ZEI OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3ZEI FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=AWH:3-[(Z)-[(5Z)-5-[[2-(2-HYDROXY-2-OXOETHYLOXY)PHENYL]METHYLIDENE]-3-METHYL-4-OXIDANYLIDENE-1,3-THIAZOLIDIN-2-YLIDENE]AMINO]BENZOIC+ACID'>AWH</scene>, <scene name='pdbligand=MPD:(4S)-2-METHYL-2,4-PENTANEDIOL'>MPD</scene>, <scene name='pdbligand=PLP:PYRIDOXAL-5-PHOSPHATE'>PLP</scene></td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Cysteine_synthase Cysteine synthase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.5.1.47 2.5.1.47] </span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3zei FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3zei OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3zei RCSB], [http://www.ebi.ac.uk/pdbsum/3zei PDBsum]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The cysteine biosynthetic pathway is absent in humans but essential in microbial pathogens, suggesting that it provides potential targets for the development of novel antibacterial compounds. CysK1 is a pyridoxalphosphate-dependent O-acetyl sulfhydrylase, which catalyzes the formation of L-cysteine from O-acetyl serine and hydrogen sulfide. Here we report nanomolar thiazolidine inhibitors of M. tuberculosis CysK1 developed by rational inhibitor design. The thiazolidine compounds were discovered using the crystal structure of a CysK1-peptide inhibitor complex as template. Pharmacophore modelling and subsequent in vitro screening gave an initial hit compound 2 (IC50 of 103.8 nM) which was subsequently optimized by a combination of protein crystallography, modelling, and synthetic chemistry. Hit expansion of 2 by chemical synthesis led to improved thiazolidine inhibitors with an IC50 value of 19 nM for the best compound, a 150 fold higher potency than the natural peptide inhibitor (IC50 2.9 microM). | |||
Structure-Guided Design of Novel Thiazolidine Inhibitors of O-Acetyl Serine Sulfhydrylase from Mycobacterium tuberculosis.,Poyraz O, Jeankumar VU, Saxena S, Schnell R, Haraldsson M, Yogeeswari P, Sriram D, Schneider G J Med Chem. 2013 Jul 23. PMID:23879381<ref>PMID:23879381</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
== References == | |||
== | <references/> | ||
__TOC__ | |||
</StructureSection> | |||
[[Category: Cysteine synthase]] | [[Category: Cysteine synthase]] | ||
[[Category: Mycobacterium tuberculosis]] | [[Category: Mycobacterium tuberculosis]] | ||
[[Category: Poyraz, O | [[Category: Poyraz, O]] | ||
[[Category: Schneider, G | [[Category: Schneider, G]] | ||
[[Category: Schnell, R | [[Category: Schnell, R]] | ||
[[Category: Hydrolase]] | [[Category: Hydrolase]] | ||
[[Category: Inhibitor]] | [[Category: Inhibitor]] | ||
Revision as of 09:11, 21 December 2014
Structure of the Mycobacterium tuberculosis O-Acetylserine Sulfhydrylase (OASS) CysK1 in complex with a small molecule inhibitor
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