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

Significance Last year, 1.6 × 106 people died from tuberculosis (TB), and about 10 × 106 became infected with the causative bacterium Mycobacterium tuberculosis and 460,000 of them with multidrug-resistant bacteria. Bedaquiline, a new anti-TB drug, developed to combat multidrug-resistant TB, kills M. tuberculosis by preventing the operation of its molecular machine for generating adenosine triphosphate (ATP), the fuel of life, without affecting the equivalent human machine. Here, we describe the molecular structure of the module in the mycobacterial machine where ATP is generated. Differences between this module and the equivalent human module can now be exploited to develop new anti-TB drugs, unrelated to bedaquiline, that also may help to prevent and cure TB by inhibiting the formation of ATP. The crystal structure of the F1-catalytic domain of the adenosine triphosphate (ATP) synthase has been determined from Mycobacterium smegmatis which hydrolyzes 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 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 F1 domain in Mycobacterium tuberculosis, prevent ATP synthesis, and inhibit the growth of the pathogen.