Structure−Function Analysis of a Phage Display-Derived Peptide That Binds to Insulin-like Growth Factor Binding Protein 1
- 29 June 2001
- journal article
- Published by American Chemical Society (ACS) in Biochemistry
- Vol. 40 (29) , 8487-8498
- https://doi.org/10.1021/bi0103866
Abstract
Highly structured, peptide antagonists of the interaction between insulin-like growth factor 1 (IGF-I) and IGF binding protein 1 (IGFBP-1) have recently been discovered by phage display of naïve peptide libraries [Lowman, H. B., et al. (1998) Biochemistry37, 8870−8878]. We now report a detailed analysis of the features of this turn−helix peptide motif that are necessary for IGFBP-1 binding and structural integrity. Further rounds of phage randomization indicate the importance of residues contributing to a hydrophobic patch on one face of the helix. Alanine-scanning substitutions confirm that the hydrophobic residues are necessary for binding. However, structural analysis by NMR spectroscopy indicates that some of these analogues are less well folded. Structured, high-affinity analogues that lack the disulfide bond were prepared by introducing a covalent constraint between side chains at positions i and i + 7 or i + 8 within the helix. Analogues based on this scaffold demonstrate that a helical conformation is present in the bound state, and that hydrophobic side chains in this helix, and residues immediately preceding it, interact with IGFBP-1. By comparison of alanine scanning data for IGF-I and the turn−helix peptide, we propose a model for common surface features of these molecules that recognize IGFBP-1.Keywords
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