Structural Basis of Bcl-x(L) Recognition by a BH3-Mimetic alpha/beta-Peptide Generated by Sequence-Based Design

Lee, EF; Smith, BJ; Horne, WS; Mayer, KN; Evangelista, M; Colman, PM; Gellman, SH; Fairlie, WD

Author(s): Lee, EF; Smith, BJ; Horne, WS; Mayer, KN; Evangelista, M; Colman, PM; Gellman, SH; Fairlie, WD;
Details: Publication Year 2011-09-05,Volume 12,Issue #13,Page 2025-2032
Journal Title: CHEMBIOCHEM
Publication Type: Journal Article
Abstract: The crystal structure of a complex between the prosurvival protein Bcl-x(L) and an alpha/beta-peptide 21-mer is described. The alpha/beta-peptide contains six beta-amino acid residues distributed periodically throughout the sequence and adopts an alpha-helix-like conformation that mimics the bioactive shape of the Puma BH3 domain. The alpha/beta-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 alpha/beta-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 alpha/beta-peptide to engage Bcl-x(L) with high affinity. Geometric comparisons of the BH3-mimetic alpha/beta-peptide with alpha/beta-peptides in helix-bundle assemblies provide insight on the conformational plasticity of backbones that contain combinations of alpha- and beta-amino acid residues. The BH3-mimetic alpha/beta-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.
Publisher: WILEY-BLACKWELL
Keywords: PROTEIN SURFACE RECOGNITION; QUATERNARY STRUCTURE; MAXIMUM-LIKELIHOOD; BH3-ONLY PROTEINS; HELIX BUNDLE; BH3 DOMAINS; COMPLEX; MCL-1; APOPTOSIS; BCL-2
Publisher's Version: https://doi.org/10.1002/cbic.201100314
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2011-09-05 12:00:00