4A1U

Crystal structure of alpha-beta-foldamer 2c in complex with Bcl-xL

Summary for 4A1U

• Entry DOI: 10.2210/pdb4a1u/pdb
• Related: 1BXL 1G5J 1LXL 1MAZ 1R2D 1R2E 1R2G 1R2H 1R2I 1YSG 1YSI 1YSN 2B48 2YJ1 4A1W
• Descriptor: BCL-2-LIKE PROTEIN 1, ALPHA-BETA-FOLDAMER 2C, CHLORIDE ION, ... (5 entities in total)
• Functional Keywords: apoptosis, alpha-helix, bh3, mimicry
• Biological source: HOMO SAPIENS (HUMAN); More
• Total number of polymer chains: 2
• Total formula weight: 20437.62

Authors

Boersma, M.D.,Haase, H.S.,Kaufman, K.J.,Horne, W.S.,Lee, E.F.,Clarke, O.B.,Smith, B.J.,Colman, P.M.,Gellman, S.H.,Fairlie, W.D. (deposition date: 2011-09-20, release date: 2011-12-28, Last modification date: 2023-12-20)

Primary citation

Boersma, M.D.,Haase, H.S.,Peterson-Kaufman, K.J.,Lee, E.F.,Clarke, O.B.,Colman, P.M.,Smith, B.J.,Horne, W.S.,Fairlie, W.D.,Gellman, S.H.
Evaluation of Diverse Alpha/Beta-Backbone Patterns for Functional Alpha-Helix Mimicry: Analogues of the Bim Bh3 Domain.
J.Am.Chem.Soc., 134:315-, 2012

PubMed Abstract: Peptidic oligomers that contain both α- and β-amino acid residues, in regular patterns throughout the backbone, are emerging as structural mimics of α-helix-forming conventional peptides (composed exclusively of α-amino acid residues). Here we describe a comprehensive evaluation of diverse α/β-peptide homologues of the Bim BH3 domain in terms of their ability to bind to the BH3-recognition sites on two partner proteins, Bcl-x(L) and Mcl-1. These proteins are members of the anti-apoptotic Bcl-2 family, and both bind tightly to the Bim BH3 domain itself. All α/β-peptide homologues retain the side-chain sequence of the Bim BH3 domain, but each homologue contains periodic α-residue → β(3)-residue substitutions. Previous work has shown that the ααβαααβ pattern, which aligns the β(3)-residues in a 'stripe' along one side of the helix, can support functional α-helix mimicry, and the results reported here strengthen this conclusion. The present study provides the first evaluation of functional mimicry by ααβ and αααβ patterns, which cause the β(3)-residues to spiral around the helix periphery. We find that the αααβ pattern can support effective mimicry of the Bim BH3 domain, as manifested by the crystal structure of an α/β-peptide bound to Bcl-x(L), affinity for a variety of Bcl-2 family proteins, and induction of apoptotic signaling in mouse embryonic fibroblast extracts. The best αααβ homologue shows substantial protection from proteolytic degradation relative to the Bim BH3 α-peptide.

PubMed: 22040025
DOI: 10.1021/JA207148M

Experimental method

X-RAY DIFFRACTION (1.54 Å)