The structure of the catalytic domain of the ATP synthase from <i>Mycobacterium smegmatis</i> is a target for developing antitubercular drugs.
Proceedings of the National Academy of Sciences of the United States of America
National Academy of Sciences
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Zhang, A. T., Montgomery, M., Leslie, A. G., Cook, G. M., & Walker, J. (2019). The structure of the catalytic domain of the ATP synthase from <i>Mycobacterium smegmatis</i> is a target for developing antitubercular drugs.. Proceedings of the National Academy of Sciences of the United States of America, 116 (10), 4206-4211. https://doi.org/10.1073/pnas.1817615116
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.
Humans, Mycobacterium smegmatis, Mycobacterium tuberculosis, Tuberculosis, Multidrug-Resistant, ATP Synthetase Complexes, Bacterial Proteins, Antitubercular Agents, Drug Resistance, Multiple, Bacterial, Diarylquinolines
This work was supported by the Medical Research Council, U. K. by grants MC_U105663150 and MR/M009858/1 to J. E. W., and MC_U105184325 to A. G. W. L.; and by the European Drug Initiative on Channels and Transporters via contract HEALTHF4- 2007-201924 (EDICT) to J. E. W. G. M. C. was supported by a James Cook Fellowship from The Royal Society of New Zealand.
External DOI: https://doi.org/10.1073/pnas.1817615116
This record's URL: https://www.repository.cam.ac.uk/handle/1810/288900