Protein-protein interactions among Bcl-2 family proteins regulate apoptosis. Anti-apoptotic members of the family, including Bcl-2, Bcl-xL, Bcl-w, Mcl-1, and Bfl-1, sequester pro-apoptotic family members by binding tightly to an amphipathic alpha helix within them, blocking pro-death functions. Through this mechanism, overexpression of the anti-apoptotic proteins is implicated in oncogenesis and resistance to chemotherapy. Tight-binding and selective inhibitors of Bcl-2 family proteins can be used to diagnose the Bcl-2 dependencies of cancer cells and may be developed as therapeutics. The challenge of designing peptides that function as high-affinity and selective inhibitors of specific Bcl-2 family proteins poses a fundamental, challenging problem in protein engineering and a good opportunity to study principles of protein-peptide recognition. I will describe features of Bcl-2 family protein interactions and discuss approaches we have developed that integrate computational structure-based modeling with high-throughput screening to generate peptide-based inhibitors.

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