title: Structural basis of Bcl-xL recognition by a BH3-mimetic α/β-peptide generated by sequence-based design.
abstract: 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.
authors: Structural Biology Division, The Walter and Eliza Hall Institute for Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia.
authors: Erinna F
authors: EF
authors: Lee
authors: Brian J
authors: BJ
authors: Smith
authors: W Seth
authors: WS
authors: Horne
authors: Kelsey N
authors: KN
authors: Mayer
authors: Marco
authors: M
authors: Evangelista
authors: Peter M
authors: PM
authors: Colman
authors: Samuel H
authors: SH
authors: Gellman
authors: W Douglas
authors: WD
authors: Fairlie
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism; D057786:Peptidomimetics / Q000737:chemistry; D017433:Protein Structure, Secondary; D011518:Proto-Oncogene Proteins / Q000737:chemistry* / Q000378:metabolism; D051020:bcl-X Protein / Q000737:chemistry* / Q000378:metabolism
chemical_list: C474007:Bax protein (53-86); D010446:Peptide Fragments; D010455:Peptides; D057786:Peptidomimetics; D011518:Proto-Oncogene Proteins; D051020:bcl-X Protein