title: Chimeric (alpha/beta + alpha)-peptide ligands for the BH3-recognition cleft of Bcl-XL: critical role of the molecular scaffold in protein surface recognition.
abstract: Molecules that bind to specific surface sites on proteins are of great interest from both fundamental and practical perspectives. We are exploring a ligand development strategy that is based on oligomers with discrete folding propensities ("foldamers"); we target a specific cleft on the cancer-associated protein Bcl-xL because this system is well characterized structurally. In vivo, this cleft binds to alpha-helical segments (BH3 domains) of other proteins. We evaluated several types of helical foldamer, built entirely from beta-amino acid residues or from mixtures of alpha- and beta-amino acid residues, and ultimately identified foldamers in the latter class that bind very tightly to Bcl-xL. Our results suggest that combining different types of foldamer backbones will be an effective and general strategy for creating high-affinity and specific ligands for protein surface sites.
authors.affiliation: Department of Chemistry, University of Wisconsin, Madison, Wisconsin 53706, USA.
authors.forename: Jack D
authors.initials: JD
authors.lastname: Sadowsky
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Schmitt
authors.forename: Hee-Seung
authors.initials: HS
authors.lastname: Lee
authors.forename: Naoki
authors.initials: N
authors.lastname: Umezawa
authors.forename: Shaomeng
authors.initials: S
authors.lastname: Wang
authors.forename: York
authors.initials: Y
authors.lastname: Tomita
authors.forename: Samuel H
authors.initials: SH
authors.lastname: Gellman
mesh_terms: D001667:Binding, Competitive; D008024:Ligands; D008565:Membrane Proteins / Q000737:chemistry* / Q000378:metabolism; D019906:Nuclear Magnetic Resonance, Biomolecular; D010455:Peptides / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D017433:Protein Structure, Secondary; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics; D013237:Stereoisomerism
chemical_list: D008024:Ligands; D008565:Membrane Proteins; D010455:Peptides; D011993:Recombinant Fusion Proteins