@article{c3ac18d78df44d7eb1887d7b00f4970e,
title = "Inhibiting Mycobacterium tuberculosis CoaBC by targeting an allosteric site",
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.",
author = "Vitor Mendes and Green, {Simon R.} and Evans, {Joanna C.} and Jeannine Hess and Michal Blaszczyk and Christina Spry and Owain Bryant and James Cory-Wright and Chan, {Daniel S.H.} and Torres, {Pedro H.M.} and Zhe Wang and Navid Nahiyaan and Sandra O{\textquoteright}Neill and Sebastian Damerow and John Post and Tracy Bayliss and Lynch, {Sasha L.} and Coyne, {Anthony G.} and Ray, {Peter C.} and Chris Abell and Rhee, {Kyu Y.} and Boshoff, {Helena I.M.} and Barry, {Clifton E.} and Valerie Mizrahi and Wyatt, {Paul G.} and Blundell, {Tom L.}",
note = "Funding Information: We dedicate this work to the memory of Professor Chris Abell who sadly died suddenly on Monday 26th October at the age of 62. Chris developed highly interdisciplinary research focused on understanding the mechanisms of key enzymes and the development of chemistry for structure-guided fragment-based drug discovery. He leaves a lasting legacy through his work and the numerous scientists whose careers he helped to shape. This work was funded by the Bill and Melinda Gates Foundation HIT-TB (OPP1024021) and SHORTEN-TB (OPP1158806) (VMendes, JCE and MB) and in part by the Intramural Research Program of NIH, NIAID (HIMB and CEB) and the South African Medical Research Council and National Research Foundation (VMizrahi). J.H. was financially supported by Swiss National Science Foundation (SNSF Early PostDoc. Mobility fellowship, P2ZHP2_164947) and the Marie Curie Research Grants Scheme, EU H2020 Framework Programme (H2020-MSCA-IF-2017, ID: 789607). C.S. was funded in part by a NHMRC Overseas Biomedical Fellowship (1016357) and in part by the Bill and Melinda Gates Foundation HIT-TB (OPP1024021). CoaBC screening was funded by a MRC-CinC (grant no. MC_PC_14099). T.L.B. is funded by the Wellcome Trust (Wellcome Trust Investigator Award 200814_Z_16_Z: RG83114). The authors would like to thank the Diamond Light Source for beam-time (proposals mx9537, mx14043, mx18548), the Seattle Structural Genomics Centre for Infectious Disease for kindly providing the M. smegmatis CoaB plasmid and Dr. Nuno Empadinhas for graciously providing the DNA of M. smegmatis mc2 155. Publisher Copyright: {\textcopyright} 2021, The Author(s).",
year = "2021",
month = dec,
day = "1",
doi = "10.1038/s41467-020-20224-x",
language = "English",
volume = "12",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",
}