6thc: Difference between revisions
New page: '''Unreleased structure''' The entry 6thc is ON HOLD until Paper Publication Authors: Mendes, V., Blaszczyk, M., Bryant, O., Cory-Wright, J., Blundell, T.L. Description: Crystal struct... |
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==Crystal structure of Mycobacterium smegmatis CoaB in complex with CTP and (4-hydroxyphenyl)(2,3,4-trihydroxyphenyl)methanone== | |||
<StructureSection load='6thc' size='340' side='right'caption='[[6thc]], [[Resolution|resolution]] 2.03Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6thc]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycolicibacterium_smegmatis Mycolicibacterium smegmatis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6THC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6THC 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]] 2.033Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=CTP:CYTIDINE-5-TRIPHOSPHATE'>CTP</scene>, <scene name='pdbligand=N9N:(4-hydroxyphenyl)-[2,3,4-tris(oxidanyl)phenyl]methanone'>N9N</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=6thc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6thc OCA], [https://pdbe.org/6thc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6thc RCSB], [https://www.ebi.ac.uk/pdbsum/6thc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6thc ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/COABC_MYCS2 COABC_MYCS2] Catalyzes two sequential steps in the biosynthesis of coenzyme A. In the first step cysteine is conjugated to 4'-phosphopantothenate to form 4-phosphopantothenoylcysteine. In the second step the latter compound is decarboxylated to form 4'-phosphopantotheine.[HAMAP-Rule:MF_02225] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Coenzyme A (CoA) is a fundamental co-factor for all life, involved in numerous metabolic pathways and cellular processes, and its biosynthetic pathway has raised substantial interest as a drug target against multiple pathogens including Mycobacterium tuberculosis. The biosynthesis of CoA is performed in five steps, with the second and third steps being catalysed in the vast majority of prokaryotes, including M. tuberculosis, by a single bifunctional protein, CoaBC. Depletion of CoaBC was found to be bactericidal in M. tuberculosis. Here we report the first structure of a full-length CoaBC, from the model organism Mycobacterium smegmatis, describe how it is organised as a dodecamer and regulated by CoA thioesters. A high-throughput biochemical screen focusing on CoaB identified two inhibitors with different chemical scaffolds. Hit expansion led to the discovery of potent and selective inhibitors of M. tuberculosis CoaB, which we show to bind to a cryptic allosteric site within CoaB. | |||
Inhibiting Mycobacterium tuberculosis CoaBC by targeting an allosteric site.,Mendes V, Green SR, Evans JC, Hess J, Blaszczyk M, Spry C, Bryant O, Cory-Wright J, Chan DS, Torres PHM, Wang Z, Nahiyaan N, O'Neill S, Damerow S, Post J, Bayliss T, Lynch SL, Coyne AG, Ray PC, Abell C, Rhee KY, Boshoff HIM, Barry CE 3rd, Mizrahi V, Wyatt PG, Blundell TL Nat Commun. 2021 Jan 8;12(1):143. doi: 10.1038/s41467-020-20224-x. PMID:33420031<ref>PMID:33420031</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 6thc" style="background-color:#fffaf0;"></div> | ||
[[Category: | == References == | ||
[[Category: | <references/> | ||
[[Category: | __TOC__ | ||
[[Category: | </StructureSection> | ||
[[Category: Large Structures]] | |||
[[Category: Mycolicibacterium smegmatis]] | |||
[[Category: Blaszczyk M]] | |||
[[Category: Blundell TL]] | |||
[[Category: Bryant O]] | |||
[[Category: Cory-Wright J]] | |||
[[Category: Mendes V]] | |||
Latest revision as of 16:02, 24 January 2024
Crystal structure of Mycobacterium smegmatis CoaB in complex with CTP and (4-hydroxyphenyl)(2,3,4-trihydroxyphenyl)methanoneCrystal structure of Mycobacterium smegmatis CoaB in complex with CTP and (4-hydroxyphenyl)(2,3,4-trihydroxyphenyl)methanone
Structural highlights
FunctionCOABC_MYCS2 Catalyzes two sequential steps in the biosynthesis of coenzyme A. In the first step cysteine is conjugated to 4'-phosphopantothenate to form 4-phosphopantothenoylcysteine. In the second step the latter compound is decarboxylated to form 4'-phosphopantotheine.[HAMAP-Rule:MF_02225] Publication Abstract from PubMedCoenzyme A (CoA) is a fundamental co-factor for all life, involved in numerous metabolic pathways and cellular processes, and its biosynthetic pathway has raised substantial interest as a drug target against multiple pathogens including Mycobacterium tuberculosis. The biosynthesis of CoA is performed in five steps, with the second and third steps being catalysed in the vast majority of prokaryotes, including M. tuberculosis, by a single bifunctional protein, CoaBC. Depletion of CoaBC was found to be bactericidal in M. tuberculosis. Here we report the first structure of a full-length CoaBC, from the model organism Mycobacterium smegmatis, describe how it is organised as a dodecamer and regulated by CoA thioesters. A high-throughput biochemical screen focusing on CoaB identified two inhibitors with different chemical scaffolds. Hit expansion led to the discovery of potent and selective inhibitors of M. tuberculosis CoaB, which we show to bind to a cryptic allosteric site within CoaB. Inhibiting Mycobacterium tuberculosis CoaBC by targeting an allosteric site.,Mendes V, Green SR, Evans JC, Hess J, Blaszczyk M, Spry C, Bryant O, Cory-Wright J, Chan DS, Torres PHM, Wang Z, Nahiyaan N, O'Neill S, Damerow S, Post J, Bayliss T, Lynch SL, Coyne AG, Ray PC, Abell C, Rhee KY, Boshoff HIM, Barry CE 3rd, Mizrahi V, Wyatt PG, Blundell TL Nat Commun. 2021 Jan 8;12(1):143. doi: 10.1038/s41467-020-20224-x. PMID:33420031[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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