Work

Structural Snapshots of F 1 ‐ ATPase Catalysis in Drug Resistant Acinetobacter baumannii Reveal Novel Therapeutic Targets

Year: 2026

Type: article

Abstract: ABSTRACT Gram‐negative Acinetobacter baumannii , one of the most critical priority pathogens, has developed multiple defense mechanisms, including upregulation of drug efflux pumps powered by the proton‐motive force (pmf) or ATP. As a nonfermenting bacterium, it relies on oxidative phosphorylation, in which the F‐ATP synthase, composed of an F 1 ‐ATPase ( α 3 : β 3 : γ : ε ) and F O ‐domain ( a : b 2 : c 10 ), synthesizes ATP, the cell's currency of life. Here, we present cryo‐electron microscopy structures of the F 1 ‐ATPase captured during ATP synthesis, revealing concerted conformational changes within the α 3 : β 3 ‐catalytic head that trigger structural transitions of subunit ε and twisting of the γ : ε central stalk, coupled with spontaneous ATP formation. Molecular dynamics simulations validate and expand the ensemble of structural rearrangements underlying the rotary mechanism. The resolved intermediate states of the ε subunit reveal its role as a molecular gear, regulating ATP synthesis while simultaneously inhibiting ATP hydrolysis, essential for the pathogen to prevent wastage of ATP. These structural snapshots identify novel therapeutic targets and pave the way for rational design of selective inhibitors.

Source: The FASEB Journal

DOI: 10.1096/fj.202602735r

Authors: Khoa C. M. Le, Jan K. Marzinek, Vikneswaran Mathiyazakan, Peter J. Bond, Gerhard Grüber

Institutions: Nanyang Technological University, Agency for Science, Technology and Research, National University of Singapore, National Centre for Infectious Diseases

Language: English

Topic: ATP Synthase and ATPases Research

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $3,740