Chimeric (alpha/beta + alpha)-peptide ligands for the BH3-recognition cleft of Bcl-XL: critical role of the molecular scaffold in protein surface recognition.
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.
Sadowsky
Jack D
JD
Department of Chemistry, University of Wisconsin, Madison, Wisconsin 53706, USA.
Schmitt
Margaret A
MA
Lee
Hee-Seung
HS
Umezawa
Naoki
N
Wang
Shaomeng
S
Tomita
York
Y
Gellman
Samuel H
SH
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
D008024:Ligands; D008565:Membrane Proteins; D010455:Peptides; D011993:Recombinant Fusion Proteins