Article abstract
Nature Cell Biology 3, 183 - 191 (2001)
Published online: 17 January 2001 | doi:10.1038/35055095
Antimycin A mimics a cell-death-inducing Bcl-2 homology domain 3
Shie-Pon Tzung1, Kristine M. Kim2, Gorka Basañez4, Chris D. Giedt3, Julian Simon3, Joshua Zimmerberg4, Kam Y. J. Zhang2 & David M. Hockenbery3
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 
m 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.
- Division of Gastroenterology, Department of Medicine, University of Washington, Seattle, Washington, 98195 USA
- Division of Basic Science, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N., Seattle, Washington, 98109 USA
- Division of Clinical Research, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N., Seattle, Washington, 98109 USA
- Laboratory of Cellular and Molecular Biophysics, National Institute of Child Health and Human Disease, National Institutes of Health , Bethesda, Maryland, 20892 USA
Correspondence to: David M. Hockenbery3 e-mail: dhockenb@fhcrc.org
