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Cryo-EM structure of archazolid A bound to yeast VO V-ATPaseCryo-EM structure of archazolid A bound to yeast VO V-ATPase
Structural highlights
FunctionRNK_YEAST Accessory component of the V0 complex of vacuolar(H+)-ATPase (V-ATPase), a multisubunit enzyme composed of a peripheral complex (V1) that hydrolyzes ATP and a membrane integral complex (V0) that translocates protons (PubMed:29526695). V-ATPase is responsible for acidifying and maintaining the pH of intracellular compartments (PubMed:29526695).[1] Publication Abstract from PubMedVacuolar-type adenosine triphosphatases (V-ATPases) are proton pumps found in almost all eukaryotic cells. These enzymes consist of a soluble catalytic V(1) region that hydrolyzes ATP and a membrane-embedded V(O) 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(O) complex from Saccharomyces cerevisiae 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. Cryo-EM of the Yeast V(O) Complex Reveals Distinct Binding Sites for Macrolide V-ATPase Inhibitors.,Keon KA, Benlekbir S, Kirsch SH, Muller R, Rubinstein JL ACS Chem Biol. 2022 Mar 18;17(3):619-628. doi: 10.1021/acschembio.1c00894. Epub , 2022 Feb 11. PMID:35148071[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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