4.6 Article

Cryo-EM of the Yeast Vo Complex Reveals Distinct Binding Sites for Macrolide V-ATPase Inhibitors

期刊

ACS CHEMICAL BIOLOGY
卷 17, 期 3, 页码 619-628

出版社

AMER CHEMICAL SOC
DOI: 10.1021/acschembio.1c00894

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资金

  1. Canadian Institutes of Health Research (CIHR)
  2. Ontario Graduate Scholarship
  3. University of Toronto
  4. Canada Research Chairs program
  5. Canadian Institutes of Health Research [PJT166152]
  6. Canada Foundation for Innovation
  7. Ontario Research Fund

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V-ATPases play an important role in acidification of intracellular compartments and V-ATPase inhibitors have potential applications in cell biology research and therapy. This study determined the binding structures of V-o complex from yeast with two inhibitors, revealing different binding sites on the surface of the proton-carrying c ring.
Vacuolar-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 A(1) 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 su ests 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.

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