| Literature DB >> 33420031 |
Vitor Mendes1, Simon R Green2, Joanna C Evans3, Jeannine Hess4, Michal Blaszczyk5, Christina Spry4, Owain Bryant5, James Cory-Wright5, Daniel S-H Chan4, Pedro H M Torres5, Zhe Wang6, Navid Nahiyaan6, Sandra O'Neill2, Sebastian Damerow2, John Post2, Tracy Bayliss2, Sasha L Lynch3, Anthony G Coyne4, Peter C Ray2, Chris Abell4, Kyu Y Rhee6, Helena I M Boshoff7, Clifton E Barry3,7, Valerie Mizrahi3, Paul G Wyatt2, Tom L Blundell8.
Abstract
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.Entities:
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Year: 2021 PMID： 33420031 PMCID： PMC7794376 DOI： 10.1038/s41467-020-20224-x
Source DB: PubMed Journal: Nat Commun ISSN： 2041-1723 Impact factor: 14.919