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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-\u00c5. The structure reveals six bafilomycin A1 molecules bound to the c-ring. One bafilomycin A1 molecule engages with two <jats:italic>c<\/jats:italic> subunits and disrupts the interactions between the c-ring and subunit <jats:italic>a<\/jats:italic>, 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\u2019-hydroxyl group of bafilomycin A1 acts as a unique feature recognized by subunit <jats:italic>c<\/jats:italic>.<\/jats:p>","DOI":"10.1038\/s41467-021-22111-5","type":"journal-article","created":{"date-parts":[[2021,3,19]],"date-time":"2021-03-19T13:05:27Z","timestamp":1616159127000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":223,"title":["Molecular basis of V-ATPase inhibition by bafilomycin A1"],"prefix":"10.1038","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7342-5278","authenticated-orcid":false,"given":"Rong","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdirahman","family":"Hassan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0819-6477","authenticated-orcid":false,"given":"Chia-Hsueh","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7013-4571","authenticated-orcid":false,"given":"Xiao-Song","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0177-0803","authenticated-orcid":false,"given":"Xiaochun","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,3,19]]},"reference":[{"key":"22111_CR1","doi-asserted-by":"publisher","first-page":"1071","DOI":"10.1152\/physrev.00035.2015","volume":"96","author":"L Stransky","year":"2016","unstructured":"Stransky, L., Cotter, K. & Forgac, M. 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