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

DOI: 10.1073/pnas.1817615116 DOI Help

Authors: Alice Tianbu Zhang (The Medical Research Council Mitochondrial Biology Unit, University of Cambridge) , Martin G. Montgomery (The Medical Research Council Mitochondrial Biology Unit, University of Cambridge) , Andrew G. W. Leslie (The Medical Research Council Laboratory of Molecular Biology) , Gregory M. Cook (The Medical Research Council Mitochondrial Biology Unit, University of Cambridge; University of Otago) , John E. Walker (The Medical Research Council Mitochondrial Biology Unit, University of Cambridge)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Proceedings Of The National Academy Of Sciences , VOL 60

State: Published (Approved)
Published: January 2019
Diamond Proposal Number(s): 8547

Abstract: The crystal structure has been determined of the F1-catalytic domain of the ATP synthase from Mycobacterium smegmatis which hydrolyzes adenosine triphosphate (ATP) very poorly. The structure of the α3β3-component of the catalytic domain is similar to those in active F1-ATPases in Escherichia coli and Geobacillus stearothermophilus. However, its ε-subunit differs from those in these two active bacterial F1-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 E. coli and G. stearothermophilus, the α-helices adopt an “up” state where the α-helices enter the α3β3-domain and prevent the rotor from turning. The mycobacterial F1-ATPase is most similar to the F1-ATPase from Caldalkalibacillus thermarum, which also hydrolyzes ATP poorly. The βE-subunits in both enzymes are in the usual “open” conformation, but appear to be occupied uniquely by the combination of an ADP 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 inhibition of ATP hydrolysis. It can be envisaged that specific as yet unidentified small molecules might bind to the F1-domain in M. tuberculosis, prevent ATP synthesis and inhibit the growth of the pathogen.

Journal Keywords: Mycobacterium smegmatis; F1-ATPase; structure; inhibition; tuberculosis

Subject Areas: Biology and Bio-materials


Instruments: I04-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography

Other Facilities: Swiss Light Source European Synchrotron Radiation Facility