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

Journal Article · Tue Dec 01 00:00:00 EST 2015 · Proc. Natl. Acad. Sci. USA

DOI:https://doi.org/10.1073/pnas.1207912109· OSTI ID:1050083

Symersky, Jindrich; Osowski, Daniel; Walters, D. Eric; Mueller, David M. ^[1]

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1. Rosalind

We report the high-resolution (1.9 {angstrom}) crystal structure of oligomycin bound to the subunit c10 ring of the yeast mitochondrial ATP synthase. Oligomycin binds to the surface of the c10 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.

• Research Organization: Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
• Sponsoring Organization: National Institutes of Health (NIH)
• OSTI ID: 1050083
• Journal Information: Proc. Natl. Acad. Sci. USA, Vol. 109, Issue (35) ; 08, 2012; ISSN 0027-8424
• Country of Publication: United States
• Language: ENGLISH