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