title: Antimycin A mimics a cell-death-inducing Bcl-2 homology domain 3.
abstract: The Bcl-2-related survival proteins confer cellular resistance to a wide range of agents. Bcl-xL-expressing hepatocyte cell lines are resistant to tumour necrosis factor and anti-cancer drugs, but are more sensitive than isogenic control cells to antimycin A, an inhibitor of mitochondrial electron transfer. Computational molecular docking analysis predicted that antimycin A interacts with the Bcl-2 homology domain 3 (BH3)-binding hydrophobic groove of Bcl-xL. We demonstrate that antimycin A and a Bak BH3 peptide bind competitively to recombinant Bcl-2. Antimycin A and BH3 peptide both induce mitochondrial swelling and loss of DeltaPsim on addition to mitochondria expressing Bcl-xL. The 2-methoxy derivative of antimycin A3 is inactive as an inhibitor of cellular respiration but still retains toxicity for Bcl-xL+ cells and mitochondria. Finally, antimycin A inhibits the pore-forming activity of Bcl-x L in synthetic liposomes, demonstrating that a small non-peptide ligand can directly inhibit the function of Bcl-2-related proteins.
authors.affiliation: Division of Gastroenterology, Department of Medicine, University of Washington, Seattle, Washington, 98195 USA.
authors.forename: S P
authors.initials: SP
authors.lastname: Tzung
authors.forename: K M
authors.initials: KM
authors.lastname: Kim
authors.forename: G
authors.initials: G
authors.lastname: Basañez
authors.forename: C D
authors.initials: CD
authors.lastname: Giedt
authors.forename: J
authors.initials: J
authors.lastname: Simon
authors.forename: J
authors.initials: J
authors.lastname: Zimmerberg
authors.forename: K Y
authors.initials: KY
authors.lastname: Zhang
authors.forename: D M
authors.initials: DM
authors.lastname: Hockenbery
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000968:Antimycin A / Q000031:analogs & derivatives / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002460:Cell Line; D005434:Flow Cytometry; D022781:Hepatocytes / Q000187:drug effects / Q000648:ultrastructure; D015151:Immunoblotting; D008081:Liposomes / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D008933:Mitochondrial Swelling; D008958:Models, Molecular; D015394:Molecular Structure; D017434:Protein Structure, Tertiary; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051020:bcl-X Protein
chemical_list: D000900:Anti-Bacterial Agents; C494773:Bak1 protein, mouse; C494812:Bcl2l1 protein, mouse; D008081:Liposomes; D008565:Membrane Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051020:bcl-X Protein; D000968:Antimycin A; D000255:Adenosine Triphosphate