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TitleThe Mycobacterium abscessus F-ATP synthase structure reveals mechanistic elements enabling rational drug design to combat NTM lung disease.
Journal, issue, pagesStructure, Year 2025
Publish dateDec 30, 2025
AuthorsTuck Choy Fong / Wuan-Geok Saw / Vikneswaran Mathiyazakan / Chui Fann Wong / Gerhard Grüber /
PubMed AbstractThe 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 ...The 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 α-subunit extension involved in the inhibition of ATP hydrolysis, energy transmission via the γε-stalk, and mechanochemical coupling by the δ-subunit. The structural blueprint allows precise target engagement and optimization of hits-to-leads and existing anti-Mab inhibitors targeting the engine.
External linksStructure / PubMed:41475343
MethodsEM (single particle)
Resolution2.79 - 5.61 Å
Structure data

EMDB-65138, PDB-9vkp:
Cryo-EM structure of F-ATP synthase from Mycobacteroides abscessus (Rotational State 1)
Method: EM (single particle) / Resolution: 2.94 Å

EMDB-65139, PDB-9vkq:
Cryo-EM structure of F-ATP synthase from Mycobacteroides abscessus (Rotational State 2)
Method: EM (single particle) / Resolution: 3.41 Å

EMDB-65140, PDB-9vkr:
Cryo-EM structure of F-ATP synthase from Mycobacteroides abscessus (Rotational State 3)
Method: EM (single particle) / Resolution: 2.79 Å

EMDB-65141, PDB-9vks:
Cryo-EM structure of F-ATP synthase c-ring from Mycobacteroides abscessus (Backbone)
Method: EM (single particle) / Resolution: 5.61 Å

Chemicals

ChemComp-ATP:
ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying molecule*YM

ChemComp-MG:
Unknown entry

ChemComp-ADP:
ADENOSINE-5'-DIPHOSPHATE / ADP, energy-carrying molecule*YM

Source
  • mycobacteroides abscessus subsp. abscessus (bacteria)
KeywordsHYDROLASE / ATP synthase / membrane protein / mycobacterium abscessus / mycobacterial / nontuberculous mycobacteria / c-ring

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