Oligomycin frames a common drug-binding site in the ATP synthase
2012
Symersky, Jindrich | Osowski, Daniel | Walters, D Eric | Mueller, David M.
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.
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