RESUMEN
The crystal structure of a complex between the prosurvival protein Bcl-x(L) and an α/ß-peptide 21-mer is described. The α/ß-peptide contains six ß-amino acid residues distributed periodically throughout the sequence and adopts an α-helix-like conformation that mimics the bioactive shape of the Puma BH3 domain. The α/ß-peptide forms all of the noncovalent contacts that have previously been identified as necessary for recognition of the prosurvival protein by an authentic BH3 domain. Comparison of our α/ß-peptide:Bcl-x(L) structure with structures of complexes between native BH3 domains and Bcl-2 family proteins reveals how subtle adjustments, including variations in helix radius and helix bowing, allow the α/ß-peptide to engage Bcl-x(L) with high affinity. Geometric comparisons of the BH3-mimetic α/ß-peptide with α/ß-peptides in helix-bundle assemblies provide insight on the conformational plasticity of backbones that contain combinations of α- and ß-amino acid residues. The BH3-mimetic α/ß-peptide displays prosurvival protein-binding preferences distinct from those of Puma BH3 itself, even though these two oligomers have identical side-chain sequences. Our results suggest origins for this backbone-dependent change in selectivity.