Structural Basis of Bcl‐xL Recognition by a BH3‐Mimetic α/β‐Peptide Generated by Sequence‐Based Design

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Abstract
The crystal structure of a complex between the prosurvival protein Bcl‐xL and an α/β‐peptide 21‐mer is described. The α/β‐peptide contains six β‐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/β‐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/β‐peptide:Bcl‐xL 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/β‐peptide to engage Bcl‐xL with high affinity. Geometric comparisons of the BH3‐mimetic α/β‐peptide with α/β‐peptides in helix‐bundle assemblies provide insight on the conformational plasticity of backbones that contain combinations of α‐ and β‐amino acid residues. The BH3‐mimetic α/β‐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.

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