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TitleMolecular basis of V-ATPase inhibition by bafilomycin A1.
Journal, issue, pagesNat Commun, Vol. 12, Issue 1, Page 1782, Year 2021
Publish dateMar 19, 2021
AuthorsRong Wang / Jin Wang / Abdirahman Hassan / Chia-Hsueh Lee / Xiao-Song Xie / Xiaochun Li /
PubMed AbstractPharmacological 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 ...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.
External linksNat Commun / PubMed:33741963 / PubMed Central
MethodsEM (single particle)
Resolution3.62 Å
Structure data

22880

7khr

EMDB-22880, PDB-7khr:
Cryo-EM structure of bafilomycin A1-bound intact V-ATPase from bovine brain
Method: EM (single particle) / Resolution: 3.62 Å

Chemicals

ChemComp-MG:
Unknown entry

ChemComp-ADP:
ADENOSINE-5'-DIPHOSPHATE / ADP, energy-carrying molecule*YM / Adenosine diphosphate

ChemComp-WJP:
methyl (3R,6Z,10E,14E)-3,7,11,15,19-pentamethylicosa-6,10,14,18-tetraen-1-yl dihydrogen diphosphate

ChemComp-POV:
(2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate / phospholipid*YM / POPC

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

ChemComp-OLA:
OLEIC ACID / Oleic acid

ChemComp-WEV:
(5R)-2,4-dideoxy-1-C-{(2S,3R,4S)-3-hydroxy-4-[(2R,3S,4E,6E,9R,10S,11R,12E,14Z)-10-hydroxy-3,15-dimethoxy-7,9,11,13-tetramethyl-16-oxo-1-oxacyclohexadeca-4,6,12,14-tetraen-2-yl]pentan-2-yl}-4-methyl-5-propan-2-yl-alpha-D-threo-pentopyranose

Source
  • bos taurus (cattle)
  • Bovine (cattle)
KeywordsPROTON TRANSPORT / bafilomycin A1

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