The structure of the catalytic domain of the ATP synthase from Mycobacterium smegmatis is a target for developing antitubercular drugs.

TitleThe structure of the catalytic domain of the ATP synthase from Mycobacterium smegmatis is a target for developing antitubercular drugs.
Publication TypeJournal Article
Year of Publication2019
AuthorsZhang, AT, Montgomery, MG, Leslie, AGW, Cook, GM, Walker, JE
JournalProc Natl Acad Sci U S A
Date Published2019 Jan 25
ISSN1091-6490
Abstract

The crystal structure of the F-catalytic domain of the adenosine triphosphate (ATP) synthase has been determined from which hydrolyzes ATP very poorly. The structure of the αβ-component of the catalytic domain is similar to those in active F-ATPases in and However, its ε-subunit differs from those in these two active bacterial F-ATPases as an ATP molecule is not bound to the two α-helices forming its C-terminal domain, probably because they are shorter than those in active enzymes and they lack an amino acid that contributes to the ATP binding site in active enzymes. In and , the α-helices adopt an "up" state where the α-helices enter the αβ-domain and prevent the rotor from turning. The mycobacterial F-ATPase is most similar to the F-ATPase from , which also hydrolyzes ATP poorly. The β-subunits in both enzymes are in the usual "open" conformation but appear to be occupied uniquely by the combination of an adenosine 5'-diphosphate molecule with no magnesium ion plus phosphate. This occupation is consistent with the finding that their rotors have been arrested at the same point in their rotary catalytic cycles. These bound hydrolytic products are probably the basis of the inhibition of ATP hydrolysis. It can be envisaged that specific as yet unidentified small molecules might bind to the F domain in , prevent ATP synthesis, and inhibit the growth of the pathogen.

DOI10.1073/pnas.1817615116
Alternate JournalProc. Natl. Acad. Sci. U.S.A.
Citation Key10.1073/pnas.1817615116
PubMed ID30683723
PubMed Central IDPMC6410841
Grant ListMC_EX_MR/M009858/1 / / Medical Research Council / United Kingdom
MC_U105184325 / / Medical Research Council / United Kingdom
MC_U105663150 / / Medical Research Council / United Kingdom