Cryo-EM reveals transition states of the Acinetobacter baumannii F1-ATPase rotary subunits γ and ε, unveiling novel compound targets

• Main Authors: Le, Khoa Cong Minh, Wong, Chui Fann, Müller, Volker, Grüber, Gerhard
• Other Authors: School of Biological Sciences
• Format: Article
• Language: English
• Published: 2025
• Subjects: Medicine, Health and Life Sciences; ATP synthesis; Bioenergetics
• Online Access: https://hdl.handle.net/10356/182447
• Institution: Nanyang Technological University

Priority 1: critical WHO pathogen Acinetobacter baumannii depends on ATP synthesis and ATP:ADP homeostasis and its bifunctional F1FO-ATP synthase. While synthesizing ATP, it regulates ATP cleavage by its inhibitory ε subunit to prevent wasteful ATP consumption. We determined cryo-electron microscopy structures of the ATPase active A. baumannii F1-αßγεΔ134-139 mutant in four distinct conformational states, revealing four transition states and structural transformation of the ε's C-terminal domain, forming the switch of an ATP hydrolysis off- and an ATP synthesis on-state based. These alterations go in concert with altered motions and interactions in the catalytic- and rotary subunits of this engine. These A. baumannii interacting sites provide novel pathogen-specific targets for inhibitors, with the aim of ATP depletion and/or ATP synthesis and growth inhibition. Furthermore, the presented diversity to other bacterial F-ATP synthases extends the view of structural elements regulating such a catalyst.