title: Oligomycin frames a common drug-binding site in the ATP synthase.
abstract: We report the high-resolution (1.9 Å) crystal structure of oligomycin bound to the subunit c(10) ring of the yeast mitochondrial ATP synthase. Oligomycin binds to the surface of the c(10) ring making contact with two neighboring molecules at a position that explains the inhibitory effect on ATP synthesis. The carboxyl side chain of Glu59, which is essential for proton translocation, forms an H-bond with oligomycin via a bridging water molecule but is otherwise shielded from the aqueous environment. The remaining contacts between oligomycin and subunit c are primarily hydrophobic. The amino acid residues that form the oligomycin-binding site are 100% conserved between human and yeast but are widely different from those in bacterial homologs, thus explaining the differential sensitivity to oligomycin. Prior genetics studies suggest that the oligomycin-binding site overlaps with the binding site of other antibiotics, including those effective against Mycobacterium tuberculosis, and thereby frames a common "drug-binding site." We anticipate that this drug-binding site will serve as an effective target for new antibiotics developed by rational design.
authors.affiliation: Department of Biochemistry and Molecular Biology, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA.
authors.forename: Jindrich
authors.initials: J
authors.lastname: Symersky
authors.forename: Daniel
authors.initials: D
authors.lastname: Osowski
authors.forename: D Eric
authors.initials: DE
authors.lastname: Walters
authors.forename: David M
authors.initials: DM
authors.lastname: Mueller
mesh_terms: D025181:ATP Synthetase Complexes / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D025243:Bacterial Proton-Translocating ATPases / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites / Q000187:drug effects; D018360:Crystallography, X-Ray; D015195:Drug Design; D004926:Escherichia coli / Q000201:enzymology; D029968:Escherichia coli Proteins / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology; D009169:Mycobacterium tuberculosis / Q000201:enzymology; D009840:Oligomycins / Q000494:pharmacology*; D017433:Protein Structure, Secondary; D006180:Proton-Translocating ATPases / Q000737:chemistry* / Q000378:metabolism; D011522:Protons; D012441:Saccharomyces cerevisiae / Q000201:enzymology*; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry* / Q000378:metabolism; D025262:Vacuolar Proton-Translocating ATPases / Q000737:chemistry / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D029968:Escherichia coli Proteins; D009840:Oligomycins; D011522:Protons; D029701:Saccharomyces cerevisiae Proteins; D025181:ATP Synthetase Complexes; C521357:ATP synthase subunit C, Mycobacterium tuberculosis; C523987:ATP synthase subunit c, E coli; D025243:Bacterial Proton-Translocating ATPases; D025262:Vacuolar Proton-Translocating ATPases; D006180:Proton-Translocating ATPases