Cancer cells are characterised by their immortality, as they resist apoptosis. In patients suffering from chronic lymphocytic leukaemia, a key mediator of cancer cell immortality is BCL-2: a ‘pro-survival’ protein which blocks the activity of ‘pro-apoptotic’ proteins, such as BAX and BAK. This binding is between a cognate groove on the surface of BCL-2 and a helical BCL-2 Homology 3 (BH3) motif found on pro-apoptotic proteins.
Venetoclax is one of the first anti-cancer drugs which works by directly blocking a protein-protein interaction. Specifically, venetoclax is a BCL-2 antagonist: it binds to the cognate groove on the surface of BCL-2, competitively inhibiting interaction with BH3 motifs. This prevents the cancer cell from avoiding apoptosis and leads to cell death.
This model demonstrates the interaction between BCL-2 and venetoclax (PDB: 6O0K) and explores the mechanism by which a particular mutation in BCL-2 can allow cancer cells to develop resistance to venetoclax.
DOI: 10.1038/s41467-019-10363-1
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