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The biosynthesis of CoA is performed in five steps, with the second and third steps being catalysed in the vast majority of prokaryotes, including <jats:italic>M. tuberculosis<\/jats:italic>, by a single bifunctional protein, CoaBC. Depletion of CoaBC was found to be bactericidal in <jats:italic>M. tuberculosis<\/jats:italic>. Here we report the first structure of a full-length CoaBC, from the model organism <jats:italic>Mycobacterium smegmatis<\/jats:italic>, 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 <jats:italic>M. tuberculosis<\/jats:italic> CoaB, which we show to bind to a cryptic allosteric site within CoaB.<\/jats:p>","DOI":"10.1038\/s41467-020-20224-x","type":"journal-article","created":{"date-parts":[[2021,1,8]],"date-time":"2021-01-08T11:13:01Z","timestamp":1610104381000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Inhibiting Mycobacterium tuberculosis CoaBC by targeting an allosteric site"],"prefix":"10.1038","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2734-2444","authenticated-orcid":false,"given":"Vitor","family":"Mendes","sequence":"first","affiliation":[]},{"given":"Simon R.","family":"Green","sequence":"additional","affiliation":[]},{"given":"Joanna C.","family":"Evans","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5916-0728","authenticated-orcid":false,"given":"Jeannine","family":"Hess","sequence":"additional","affiliation":[]},{"given":"Michal","family":"Blaszczyk","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8156-7070","authenticated-orcid":false,"given":"Christina","family":"Spry","sequence":"additional","affiliation":[]},{"given":"Owain","family":"Bryant","sequence":"additional","affiliation":[]},{"given":"James","family":"Cory-Wright","sequence":"additional","affiliation":[]},{"given":"Daniel S-H.","family":"Chan","sequence":"additional","affiliation":[]},{"given":"Pedro H. 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