Structural basis of Bcl-xL recognition by a BH3-mimetic ?/?-peptide generated by sequence-based design.

ABSTRACT: The crystal structure of a complex between the prosurvival protein Bcl-x(L) and an ?/?-peptide 21-mer is described. The ?/?-peptide contains six ?-amino acid residues distributed periodically throughout the sequence and adopts an ?-helix-like conformation that mimics the bioactive shape of the Puma BH3 domain. The ?/?-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 ?/?-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 ?/?-peptide to engage Bcl-x(L) with high affinity. Geometric comparisons of the BH3-mimetic ?/?-peptide with ?/?-peptides in helix-bundle assemblies provide insight on the conformational plasticity of backbones that contain combinations of ?- and ?-amino acid residues. The BH3-mimetic ?/?-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.

SUBMITTER: Lee EF 

PROVIDER: S-EPMC3263372 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature