Crystal structure of ABT-737 complexed with Bcl-x_L: implications for selectivity of antagonists of the Bcl-2 family

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Many cancers possess defects in their apoptotic machinery that provide them with a survival advantage.¹ Hence, one strategy for therapeutic intervention is to develop molecules that activate the cell death pathways. The Bcl-2 pro-survival proteins (e.g. Bcl-2, Bcl-x_L, Mcl-1) are attractive drug targets as their overexpression is observed in many tumours and contributes to chemo- and radio therapy resistance. Although there is controversy over how pro-survival Bcl-2 proteins function,^{2, 3} it is generally agreed that apoptosis is initiated by the binding of the pro-death BH3-only proteins to the pro-survival molecules. These interactions are mediated by the BH3 domain of the BH3-only proteins (Supplementary Figure 1) inserting into a hydrophobic groove on the surface of pro-survival proteins. Structural analyses of BH3 domain:pro-survival protein complexes show that four conserved hydrophobic residues (h1–h4) on one face of a helix insert into hydrophobic pockets (p1–p4) within the hydrophobic groove, while an aspartate makes a salt bridge with a conserved arginyl residue on the pro-survival molecules.^{4, 5, 6} It has also been shown that BH3 domains possess selectivity for different pro-survival proteins,⁷ and this has important implications for whether apoptosis occurs.⁸ For example, both Bcl-x_L and Mcl-1 must be neutralized for Bak-mediated apoptosis in some cell types.⁸

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