Oligomycin Frames a Common Drug-Binding Site in the ATP Synthase
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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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Oligomycin inhibits ATP synthesis by binding to the subunit-c chain in contact with the proton half-channels formed by subunit-a of ATP synthase.
“Oligomycin inhibits ATP synthesis by binding to the subunit-c chain in contact with the proton half-channels formed by subunit-a of ATP synthase [43].”
From Proliferating Astrocytes in Primary Culture Do Not Depend upon Mitochondrial Respiratory Complex I Activity or Oxidative Phosphorylation (2023) · cites this paper as [43]
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Cites
A Diarylquinoline Drug Active on the ATP Synthase of <i>Mycobacterium tuberculosis</i>
Andries, K., Verhasselt, P., Guillemont, J., Göhlmann, H. W. H., Neefs, J.-M., Winkler, H., Van Gestel, J., Timmerman, P., Zhu, M., Lee, E., et al. (2005) · Science · doi:10.1126/science.1106753 · Cited by 2,191 · cited 2× · see citing works
“Strains resistant against R207910 were isolated, and three independent mutations in the gene encoding subunit-c, Asp26Val, Ala61Pro, Ile64Met (yeast numbering system), were identified as being responsible for conferring resistance to the drug (25, 27).”
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Research works printed but not linked: 2
- Palmer RA, Potter BS (2008) X-ray structures and absolute configurations of the an- tibiotics oligomycins A, B, and C: Inhibitors of ATP synthase. J Chem Crystallogr 38(4): 243-253.
- Allen FH (2002) The Cambridge Structural Database: A quarter of a million crystal structures and rising. Acta Crystallogr B 58(Pt 3 Pt 1):380-388.
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Bonora, M., Wieckowski, M. R., Chinopoulos, C., Kepp, O., Kroemer, G., Galluzzi, L., & Pinton, P. (2015) · Oncogene · doi:10.1038/onc.2014.96 · Cited by 330 · see citing works
Current understanding of structure, function and biogenesis of yeast mitochondrial ATP synthase
Artika, I. M. (2019) · Journal of Bioenergetics and Biomembranes · doi:10.1007/s10863-019-09809-4 · Cited by 24 · see citing works
Post-translational modifications of the mitochondrial F 1 F O -ATPase
Nesci, S., Trombetti, F., Ventrella, V., & Pagliarani, A. (2017) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2017.08.007 · Cited by 21 · see citing works
Silva, E. A., Dalla Costa, A. P., Ruas, J. S., Siqueira-Santos, E. S., Francisco, A., & Castilho, R. F. (2023) · Cells · doi:10.3390/cells12050683 · Cited by 5 · see citing works
- Authors
- Symersky, J., Osowski, D., Walters, D. E., & Mueller, D. M.
- Affiliations
- Rosalind Franklin University of Medicine and Science (US)
- Department of Biochemistry and Molecular Biology and
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2012-08-06
- Volume
- 109
- Issue
- 35
- Pages
- 13961-13965
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3435195
- OpenAlex
- W1981883819
- Cited by
- 269
- References
- 1
- Citations by year
- 2026: 34 · 2025: 29 · 2024: 21 · 2023: 26 · 2022: 19 · 2021: 26 · 2020: 19 · 2019: 21 · 2018: 12 · 2017: 13 · 2016: 11 · 2015: 13 · 2014: 16 · 2013: 8
- FWCI
- 4.45
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Energy (W - 31 - 109 - Eng - 38)
- Office of Science (W-31-109-ENG-38)
- National Institute of General Medical Sciences (R01GM066223)
- Basic Energy Sciences (W-31-109-Eng38)
- Argonne National Laboratory (W-31-109-ENG-38)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › ATP Synthase and ATPases Research
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- oligomycin, ATP synthase, drug binding sites, crystal structure, proton translocation, ATP synthesis inhibition, mitochondrial ATP synthase, yeast, antibiotic targets, Mycobacterium tuberculosis, rational drug design
- MeSH terms
- Animals, Anti-Bacterial Agents, Binding Sites, Escherichia coli, Proton-Translocating ATPases, Humans, Hydrogen Bonding, Mitochondria, Mycobacterium tuberculosis, Oligomycins, Protons, Saccharomyces cerevisiae, Drug Design, Protein Structure, Secondary, Crystallography, X-Ray, ATP Synthetase Complexes, Bacterial Proton-Translocating ATPases, Vacuolar Proton-Translocating ATPases, Saccharomyces cerevisiae Proteins, Escherichia coli Proteins
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