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Inhibiting Mycobacterium tuberculosis CoaBC by targeting an allosteric site

DOI: 10.1038/s41467-020-20224-x DOI Help

Authors: Vitor Mendes (University of Cambridge) , Simon R. Green (University of Dundee) , Joanna C. Evans (University of Cape Town) , Jeannine Hess (University of Cambridge) , Michael Blaszczyk (University of Cambridge) , Christina Spry (University of Cambridge) , Owain Bryant (University of Cambridge) , James Cory-Wright (University of Cambridge) , Daniel S-H. Chan (University of Cambridge) , Pedro H. M. Torres (University of Cambridge) , Zhe Wang (Weill Cornell Medical College) , Navid Nahiyaan (Weill Cornell Medical College) , Sandra O’neill (University of Dundee) , Sebastian Damerow (University of Dundee) , John Post (University of Dundee) , Tracy Bayliss (University of Dundee) , Sasha L. Lynch (University of Cape Town) , Anthony G. Coyne (University of Cambridge) , Peter C. Ray (University of Dundee) , Chris Abell (University of Cambridge) , Kyu Y. Rhee (Weill Cornell Medical College) , Helena I. M. Boshoff (National Institute of Allergy and Infectious Disease, National Institutes of Health) , Clifton E. Barry (University of Cape Town; National Institute of Allergy and Infectious Disease, National Institutes of Health) , Valerie Mizrahi (University of Cape Town) , Paul G. Wyatt (University of Dundee) , Tom L. Blundell (University of Cambridge)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Communications , VOL 12

State: Published (Approved)
Published: January 2021
Diamond Proposal Number(s): 9537 , 14043 , 18548

Open Access Open Access

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.

Journal Keywords: Drug discovery; Enzymes; X-ray crystallography

Diamond Keywords: Tuberculosis (TB); Bacteria; Enzymes

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I02-Macromolecular Crystallography , I03-Macromolecular Crystallography

Added On: 25/01/2021 15:50

Documents:
s41467-020-20224-x.pdf

Discipline Tags:

Catalysis Life Sciences & Biotech Health & Wellbeing Drug Discovery Infectious Diseases Pathogens Chemistry Biochemistry

Technical Tags:

Diffraction Macromolecular Crystallography (MX)