7TAO

Cryo-EM structure of bafilomycin A1 bound to yeast VO V-ATPase

Summary for 7TAO

• Entry DOI: 10.2210/pdb7tao/pdb
• EMDB information: 25779
• Descriptor: V-type proton ATPase subunit c', V-type proton ATPase subunit c'', V0 assembly protein 1, ... (9 entities in total)
• Functional Keywords: inhibitor, complex, proton pump, atpase, membrane protein
• Biological source: Saccharomyces cerevisiae (baker's yeast); More
• Total number of polymer chains: 15
• Total formula weight: 359022.33

Authors

Keon, K.A.,Rubinstein, J.L.,Benlekbir, S.,Kirsch, S.H.,Muller, R. (deposition date: 2021-12-21, release date: 2022-02-23, Last modification date: 2025-06-04)

Primary citation

Keon, K.A.,Benlekbir, S.,Kirsch, S.H.,Muller, R.,Rubinstein, J.L.
Cryo-EM of the Yeast V O Complex Reveals Distinct Binding Sites for Macrolide V-ATPase Inhibitors.
Acs Chem.Biol., 17:619-628, 2022

PubMed Abstract: Vacuolar-type adenosine triphosphatases (V-ATPases) are proton pumps found in almost all eukaryotic cells. These enzymes consist of a soluble catalytic V region that hydrolyzes ATP and a membrane-embedded V region responsible for proton translocation. V-ATPase activity leads to acidification of endosomes, phagosomes, lysosomes, secretory vesicles, and the trans-Golgi network, with extracellular acidification occurring in some specialized cells. Small-molecule inhibitors of V-ATPase have played a crucial role in elucidating numerous aspects of cell biology by blocking acidification of intracellular compartments, while therapeutic use of V-ATPase inhibitors has been proposed for the treatment of cancer, osteoporosis, and some infections. Here, we determine structures of the isolated V complex from bound to two well-known macrolide inhibitors: bafilomycin A1 and archazolid A. The structures reveal different binding sites for the inhibitors on the surface of the proton-carrying c ring, with only a small amount of overlap between the two sites. Binding of both inhibitors is mediated primarily through van der Waals interactions in shallow pockets and suggests that the inhibitors block rotation of the ring. Together, these structures indicate the existence of a large chemical space available for V-ATPase inhibitors that block acidification by binding the c ring.

PubMed: 35148071
DOI: 10.1021/acschembio.1c00894

Experimental method

ELECTRON MICROSCOPY (3.2 Å)