Inhibiting Mycobacterium tuberculosis CoaBC by targeting a new allosteric site.
Mendes, V.; Green, S. R.; Evans, J. C.; Hess, J.; Blaszczyk, M.; Spry, C.; Bryant, O.; Cory-Wright, J.; Chan, D. S.-H.; Torres, P. H. M.; Wang, Z.; 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.
Show 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 inhibitors of M. tuberculosis CoaB, which we show to bind to a novel cryptic allosteric site within CoaB.
Matching journals
The top 5 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Conformational plasticity across phylogenetic clusters of RND multidrug efflux pumps and its impact on substrate specificity 96%
- Cyclodipeptide oxidase is an enzyme filament 96%
- Structural basis of S-adenosylmethionine-dependent Allosteric Transition from Active to Inactive States in Methylenetetrahydrofolate Reductase 96%
Similar papers in this journal
- Novel exported bifunctional fusion enzymes with chorismate mutase and cyclohexadienyl dehydratase activity: shikimate pathway enzymes teamed up in no man's land 95%
- The mechanism of peptidoglycan O-acetylation in Gram-negative bacteria typifies bacterial MBOAT-SGNH acyltransferases 95%
- Structural basis of substrate specificity of Helix pomatia AMP deaminase and a chimeric ADGF adenosine deaminase 95%
Similar papers in this journal
- Discovery of inhibitors for bacterial Arr enzymes ADP-ribosylating and inactivating rifamycin antibiotics 97%
- Expanding the substrate selectivity of the fimsbactin biosynthetic adenylation domain, FbsH 95%
- Integrative x-ray structure and molecular modeling for the rationalization of procaspase-8 inhibitor potency and selectivity 95%
Similar papers in this journal
- Structure and Mechanism of Avermitilol Synthase, a Sesquiterpene Cyclase that Generates a Highly Strained 6-6-3 Tricyclic Alcohol 96%
- The Crystal Structures of Bacillithiol Disulfide Reductase YpdA Reveal Structural and Functional Insight into a New Type of FAD-Containing NADPH-Dependent Oxidoreductases 95%
- Structural characterization of functionally important chloride binding sites in the marine Vibrio alkaline phosphatase 95%
Similar papers in this journal
- Differences in the regulation mechanisms of the glutamine synthetase from methanogenic archaea unveiled by structural investigations 96%
- Archaeal S-adenosyl-L-homocysteine hydrolases: structure, function and substrate preferences 95%
- Structural Insights into Cir-mediated Killing by the Antimicrobial Protein Microcin V 94%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.