Venetoclax Interaction with BCL-2

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Venetoclax is a cancer therapy agent approved for use as a BCL-2 antagonist at present. BCL-2 prevents apoptosis by binding and sequestering pro-apoptotic proteins such as BAX, BAK, BIM, and BAD. The interaction takes place when the BH3 motif of pro-apoptotic molecules engages complementary pockets (P1-P4) in the surface groove of BCL-2. Venetoclax competes with pro-apoptotic BH3 motifs for BCL-2 binding, releasing proapoptotic proteins and allowing apoptosis to occur in cells primed for death. Nonetheless, mutation of drug-binding sites is a frequent mechanism by which malignant cells evade therapies. For mutants of BCL-2 to remain resistant to venetoclax and maintain the tumor's viability they must retain the ability to bind pro-apoptotic BH3 motifs. Both G101V and F104L BCL-2 mutants possess this property, which our model explains how.