Antimycin A mimics a cell-death-inducing Bcl-2 homology domain 3
Author: ["Shie-Pon Tzung","Kristine M. Kim","Gorka Basañez","Chris D. Giedt","Julian Simon","Joshua Zimmerberg","Kam Y. J. Zhang","David M. Hockenbery"]
Publication: Nature Cell Biology
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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 ΔΨm 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-xL in synthetic liposomes, demonstrating that a small non-peptide ligand can directly inhibit the function of Bcl-2-related proteins.
Cite this article
Tzung, SP., Kim, K., Basañez, G. et al. Antimycin A mimics a cell-death-inducing Bcl-2 homology domain 3. Nat Cell Biol 3, 183–191 (2001). https://doi.org/10.1038/35055095
