Inhibiting Mycobacterium tuberculosis CoaBC by targeting an allosteric site

Inhibiting Mycobacterium tuberculosis CoaBC by targeting an allosteric site. Mendes, V., Green, S. R, Evans, J. C, Hess, J., Blaszczyk, M., Spry, C., Bryant, O., Cory-Wright, J., Chan, D. S., Torres, P. H M, Wang, Z., Nahiyaan, N., O'Neill, S., Damerow, S., Post, J., Bayliss, T., Lynch, S. L, Coyne, A. G, Ray, P. C, Abell, C., Rhee, K. Y, Boshoff, H. I M, Barry, C. E, Mizrahi, V., Wyatt, P. G, & Blundell, T. L Nature Communications, 12(1):143, Nature Publishing Group, dec, 2021.

Paper doi abstract bibtex

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.

@article{Mendes2021,
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 = {Mendes, Vitor and Green, Simon R and Evans, Joanna C and Hess, Jeannine and Blaszczyk, Michal and Spry, Christina and Bryant, Owain and Cory-Wright, James and Chan, Daniel S-H and Torres, Pedro H M and Wang, Zhe and Nahiyaan, Navid and O'Neill, Sandra and Damerow, Sebastian and Post, John and Bayliss, Tracy and Lynch, Sasha L and Coyne, Anthony G and Ray, Peter C and Abell, Chris and Rhee, Kyu Y and Boshoff, Helena I M and Barry, Clifton E and Mizrahi, Valerie and Wyatt, Paul G and Blundell, Tom L},
doi = {10.1038/s41467-020-20224-x},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Mendes et al. - 2021 - Inhibiting Mycobacterium tuberculosis CoaBC by targeting an allosteric site.pdf:pdf},
issn = {2041-1723},
journal = {Nature Communications},
keywords = {Drug discovery,Enzymes,OA,X,fund{\_}not{\_}ack,original,ray crystallography},
mendeley-tags = {OA,fund{\_}not{\_}ack,original},
month = {dec},
number = {1},
pages = {143},
pmid = {33420031},
publisher = {Nature Publishing Group},
title = {{Inhibiting Mycobacterium tuberculosis CoaBC by targeting an allosteric site}},
url = {http://www.nature.com/articles/s41467-020-20224-x},
volume = {12},
year = {2021}
}

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