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

Chembiochem. 2011 Sep 5;12(13):2025-32. doi: 10.1002/cbic.201100314. Epub 2011 Jul 8.


The crystal structure of a complex between the prosurvival protein Bcl-x(L) 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-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 α/β-peptide to engage Bcl-x(L) 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Humans
  • Mice
  • Models, Molecular
  • Molecular Sequence Data
  • Peptide Fragments / chemistry*
  • Peptide Fragments / metabolism
  • Peptides / chemistry*
  • Peptides / metabolism
  • Peptidomimetics / chemistry
  • Protein Structure, Secondary
  • Proto-Oncogene Proteins / chemistry*
  • Proto-Oncogene Proteins / metabolism
  • bcl-X Protein / chemistry*
  • bcl-X Protein / metabolism


  • Bax protein (53-86)
  • Peptide Fragments
  • Peptides
  • Peptidomimetics
  • Proto-Oncogene Proteins
  • bcl-X Protein