Conformational changes in Bcl-2 pro-survival proteins determine their capacity to bind ligands

Abstract

Antagonists of anti-apoptotic Bcl-2 family members hold promise as cancer therapeutics. Apoptosis is triggered when a peptide containing a BH3 motif or a small molecule BH3 peptidomimetic, such as ABT 737, binds to the relevant Bcl-2 family members. ABT-737 is an antagonist of Bcl-2, Bcl-xL, and Bcl-w but not of Mcl-1. Here we describe new structures of mutant BH3 peptides bound to Bcl-xL and Mcl-1. These structures suggested a rationale for the failure of ABT-737 to bind Mcl-1, but a designed variant of ABT-737 failed to acquire binding affinity for Mcl-1. Rather, it was selective for Bcl-xL, a result attributable in part to significant backbone refolding and movements of helical segments i..