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Proc Natl Acad Sci U S A. 2012 Aug 28;109(35):13961-5. doi: 10.1073/pnas.1207912109. Epub 2012 Aug 6.

Oligomycin frames a common drug-binding site in the ATP synthase.

Author information

1
Department of Biochemistry and Molecular Biology, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA.

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.

PMID:
22869738
PMCID:
PMC3435195
DOI:
10.1073/pnas.1207912109
[Indexed for MEDLINE]
Free PMC Article

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