Journal Article

Molecular basis of V-ATPase inhibition by bafilomycin A1

Li, Xiaochun, Wang, Rong, Wang, Jin, Hassan, Abdirahman, Xie, Xiao-Song, Lee, Chia-Hsueh

2021

Overview

Pharmacological inhibition of vacuolar-type H + -ATPase (V-ATPase) by its specific inhibitor can abrogate tumor metastasis, prevent autophagy, and reduce cellular signaling responses. Bafilomycin A1, a member of macrolide antibiotics and an autophagy inhibitor, serves as a specific and potent V-ATPases inhibitor. Although there are many V-ATPase structures reported, the molecular basis of specific inhibitors on V-ATPase remains unknown. Here, we report the cryo-EM structure of bafilomycin A1 bound intact bovine V-ATPase at an overall resolution of 3.6-Å. The structure reveals six bafilomycin A1 molecules bound to the c-ring. One bafilomycin A1 molecule engages with two c subunits and disrupts the interactions between the c-ring and subunit a , thereby preventing proton translocation. Structural and sequence analyses demonstrate that the bafilomycin A1-binding residues are conserved in yeast and mammalian species and the 7’-hydroxyl group of bafilomycin A1 acts as a unique feature recognized by subunit c . Bafilomycin A1, a member of macrolide antibiotics and an autophagy inhibitor, serves as a specific and potent V-ATPases inhibitor. Here authors report the cryo-EM structure of bafilomycin A1-bound V-ATPase with six bafilomycin A1 molecules bound to the c-ring and reveal the molecular basis for Bafilomycin A1 inhibition of the V-ATPase.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 101/28 / 631/154/556 / 631/45/612/1237 / 631/535/1258/1259 / Adenosine triphosphatase / Amino Acid Sequence / Animals / Antibiotics / Autophagy / Binding Sites / Biocatalysis - drug effects / Cattle / Conserved sequence / Cryoelectron Microscopy / Enzyme Inhibitors - chemistry / Enzyme Inhibitors - metabolism / Enzyme Inhibitors - pharmacology / Feature recognition / H+-transporting ATPase / Humanities and Social Sciences / Hydroxyl groups / Macrolide antibiotics / Macrolides - chemistry / Macrolides - metabolism / Macrolides - pharmacology / Metastases / Models, Molecular / Molecular Structure / multidisciplinary / Phagocytosis / Protein Binding / Protein Domains / Science / Science (multidisciplinary) / Sequence Homology, Amino Acid / Translocation / Vacuolar Proton-Translocating ATPases - antagonists & inhibitors / Vacuolar Proton-Translocating ATPases - chemistry / Vacuolar Proton-Translocating ATPases - ultrastructure / Yeast