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Publication Abstract from PubMed

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.

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 Chembiochem. 2011 Sep 5;12(13):2025-32. doi: 10.1002/cbic.201100314. Epub, 2011 Jul 8. PMID:21744457^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.