Cryo-EM structure of the Mycobacterium abscessus F1-ATPase

Abstract

The cases of lung disease caused by non-tuberculous mycobacterium Mycobacterium abscessus (Mab) are increasing and not reliably curable. Repurposing of anti-tuberculosis inhibitors brought the oxidative phosphorylation pathway with its final product ATP, formed by the essential F₁F_O-ATP synthase (subunits α₃:β₃:γ:δ:ε:a:b:b':c₉), into focus as an attractive inhibitor target against Mab. Because of the pharmacological attractiveness of this enzyme, we generated and purified a recombinant and enzymatically active Mab F₁-ATPase complex, including subunits α₃:β₃:γ:δ:ε (MabF₁-αβγδε) to achieve mechanistic, regulatory, and structural insights. The high purity of the complex enabled the first cryo-electron microscopy structure determination of the Mab F₁-ATPase complex to 7.3 Å resolution. The enzyme showed low ATP hydrolysis activity, which was stimulated by trypsin treatment. No effect was observed in the presence of the detergent lauryldimethylamine oxide.

Keywords: ATP synthase; Bioenergetics; Electron microscopy; Infectious diseases; Mycobacterium; Non-tuberculous mycobacteria.