Inhibiting Mycobacterium tuberculosis CoaBC by targeting an allosteric site.
Inhibiting Mycobacterium tuberculosis CoaBC by targeting an allosteric site.
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DOI：
10.1038/s41467-020-20224-x
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发表时间：
2021-01-08
影响因子：
16.6
通讯作者：
Blundell TL
中科院分区：
文献类型：
--
作者：
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
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. The bifunctional enzyme CoaBC catalyses the second and third step in the Coenzyme A (CoA) biosynthesis pathway and is of interest as a M. tuberculosis drug target. Here, the authors present the full-length crystal structure of Mycobacterium smegmatis CoaBC, which is regulated by CoA and CoA thioesters and forms a dodecamer and by performing a high-throughput screen they identify selective inhibitors of M. tuberculosis CoaB that bind to an allosteric site within CoaB.
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