Venetoclax (ABT-199) is a BCL-2 antagonist currently approved for cancer therapy.
BCL-2 prevents apoptosis by binding and sequestering the pro-apoptic proteins (e.g. BAX and BAK) and BH3-only proteins (e.g. BIM and BAD). The interaction occurs when a BCL-2 Homology 3 (BH3) motif of pro-apoptic molecules engage complementary pockets (P1 through P4) in the surface groove of the BCL-2.
Venetoclax competes with pro-apoptotic BH3 motifs for BCL-2 binding, releasing proapoptotic proteins and allowing apoptosis in cells primed for death.
However, mutation of drug-binding sites is a common mechanism by which malignant cells evade therapies.
For mutants of BCL-2 to be resistant to venetoclax and maintain the tumour’s viability they must retain the ability to bind pro-apoptotic BH3 motifs. Both G101V and F104L BCL-2 mutants have this property, which our model explains how.
DOI: 10.1038/s41467-019-10363-1 PDB: 6O0k
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