Antimycin A mimics a cell-death-inducing Bcl-2 homology domain 3
The Bcl-2-related survival proteins confer cellular resistance to a wide range of agents. Bcl-x L -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...
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Veröffentlicht in: | Nature cell biology 2001-02, Vol.3 (2), p.183-191 |
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Sprache: | eng |
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Zusammenfassung: | The Bcl-2-related survival proteins confer cellular resistance to a wide range of agents. Bcl-x
L
-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-x
L
. 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 Δ
Ψ
m
on addition to mitochondria expressing Bcl-x
L
. The 2-methoxy derivative of antimycin A
3
is inactive as an inhibitor of cellular respiration but still retains toxicity for Bcl-x
L
+
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. |
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ISSN: | 1465-7392 1476-4679 1476-4679 |
DOI: | 10.1038/35055095 |