Journal Article

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

Walters, D. Eric, Osowski, Daniel, Symersky, Jindrich, Mueller, David M

2012

Overview

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.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: Adenosine triphosphatase / Adenosine triphosphatases / adenosine triphosphate / Amino acids / Animals / Anti-Bacterial Agents - pharmacology / Antibiotics / Atomic interactions / Atoms / ATP / ATP Synthetase Complexes - chemistry / ATP Synthetase Complexes - metabolism / Bacteria / Bacterial Proton-Translocating ATPases - chemistry / Bacterial Proton-Translocating ATPases - metabolism / Binding sites / Binding Sites - drug effects / Biological Sciences / Crystal structure / Crystallography, X-Ray / Crystals / Drug Design / Escherichia coli - enzymology / Escherichia coli Proteins - chemistry / Escherichia coli Proteins - metabolism / Genetic mutation / Genetics / H+/K+-exchanging ATPase / H-transporting ATP synthase / Humans / Hydrogen Bonding - drug effects / hydrophobicity / Mitochondria - drug effects / Mitochondria - enzymology / Molecules / Mycobacterium tuberculosis / Mycobacterium tuberculosis - enzymology / oligomycin / Oligomycins / Oligomycins - pharmacology / Physical Sciences / Protein Structure, Secondary / Proton-Translocating ATPases - chemistry / Proton-Translocating ATPases - metabolism / Protons / Saccharomyces cerevisiae - enzymology / Saccharomyces cerevisiae Proteins - chemistry / Saccharomyces cerevisiae Proteins - metabolism / Translocation / Vacuolar Proton-Translocating ATPases - chemistry / Vacuolar Proton-Translocating ATPases - metabolism / Yeast / Yeasts