Structural highlights
FunctionATPA_MYCA9 Produces ATP from ADP in the presence of a proton gradient across the membrane. The alpha chain is a regulatory subunit. Publication Abstract from PubMedThe increasing global incidence rate of nontuberculous mycobacteria pulmonary infections is an emerging public health crisis, with Mycobacterium abscessus (Mab) being one of the most virulent and treatment-refractory of these pathogens. Mab exhibits extensive intrinsic and acquired drug resistance mechanisms that neutralize most antimicrobials against this pathogen, causing a clinical conundrum. As Mab relies on oxidative phosphorylation as its main energy source, its essential F-ATP synthase is a promising drug target but remains poorly understood due to a lack of host expression systems. Here, we present the expression, isolation, and structural characterization of Mab's F-ATP synthase. Cryo-EM reveals three nucleotide-driven rotational states at atomic resolution, highlighting key catalytic centers, a mycobacteria-specific alpha-subunit extension involved in the inhibition of ATP hydrolysis, energy transmission via the gammaepsilon-stalk, and mechanochemical coupling by the delta-subunit. The structural blueprint allows precise target engagement and optimization of hits-to-leads and existing anti-Mab inhibitors targeting the engine. The Mycobacterium abscessus F-ATP synthase structure reveals mechanistic elements enabling rational drug design to combat NTM lung disease.,Fong TC, Saw WG, Mathiyazakan V, Wong CF, Gruber G Structure. 2025 Dec 30:S0969-2126(25)00486-1. doi: 10.1016/j.str.2025.12.005. PMID:41475343[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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