Figure 3. Representative structures of BCL-2 family proteins in complex with modulators.
Small molecule inhibitors of anti-apoptotic members bind to the 4 sub-pockets (P1-P4) of the canonical groove, (a) BCL-2 in complex with an analogue of ABT-199* (PDB:4MAN), (b) BCL-XL in complex with A-1155463 (PDB:4QVX) and (c) MCL-1 in complex with S63845 (PDB:5LOF). (d) BAM7 binds to a hydrophobic N-terminal trigger site of BAX (Modified PDB:2K7W), surface properties illustrated as hydrophobic:yellow, hydrophilic:green, acidic:red, basic:blue. (e) BINDI helical bundles utilize both canonical groove and the surrounding surface to increase specificity and potency. MCL-1 in complex with a MCL-1 specific BINDI (PDB:5JSB). (f) A stapled peptide derived from the BH4 domain of BCL-2 binds to a surface of BAX distinct from both the canonical and trigger site of BAX [56]. (g) The antibody 3G11 binds BAX through interaction with an extended N-terminal trigger site inhibiting BAX conformational activation [55].