Antimycin A mimics a cell-death-inducing Bcl-2 homology domain 3

Nat Cell Biol. 2001 Feb;3(2):183-91. doi: 10.1038/35055095.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Animals
  • Anti-Bacterial Agents / pharmacology*
  • Antimycin A / analogs & derivatives
  • Antimycin A / pharmacology*
  • Apoptosis / drug effects*
  • Apoptosis / physiology
  • Cell Line
  • Flow Cytometry
  • Hepatocytes / drug effects
  • Hepatocytes / ultrastructure
  • Immunoblotting
  • Liposomes / metabolism
  • Membrane Proteins / metabolism
  • Mice
  • Mitochondria / drug effects
  • Mitochondria / metabolism*
  • Mitochondria / ultrastructure
  • Mitochondrial Swelling
  • Models, Molecular
  • Molecular Structure
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • Recombinant Proteins / metabolism
  • Transfection
  • bcl-2 Homologous Antagonist-Killer Protein
  • bcl-X Protein


  • Anti-Bacterial Agents
  • Bak1 protein, mouse
  • Bcl2l1 protein, mouse
  • Liposomes
  • Membrane Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Recombinant Proteins
  • bcl-2 Homologous Antagonist-Killer Protein
  • bcl-X Protein
  • Antimycin A
  • Adenosine Triphosphate