Bcl-XL mutations suppress cellular sensitivity to antimycin A

Cells expressing high levels of the BCL-X-L anti-apoptotic protein are preferentially killed by the mitochondrial inhibitor antimycin A ( AA). Computational modeling predicts a binding site for AA in the extended hydrophobic groove on BCL-X-L, previously identified as an interface for dimerization to BAX and related proapoptotic proteins. Here, we identify BCL-X-L hydrophobic groove mutants with normal cellular anti-apoptotic function but suppressed sensitivity to AA. The LD50 of AA for cells expressing BCL-X-L mutants directly correlates with the measured in vitro dissociation constants for AA binding. These results indicate that BCL-X-L is a principal target mediating AA cytotoxicity.