1in2

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Peptide Antagonist of IGFBP1, (i,i+7) Covalently Restrained Analog

Overview

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 naive peptide libraries, [Lowman, H. B., et al. (1998) Biochemistry 37, 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.

About this Structure

1IN2 is a Protein complex structure of sequences from [1] with ACE, NH2 and LNK as ligands. Full crystallographic information is available from OCA.

Reference

Structure-function analysis of a phage display-derived peptide that binds to insulin-like growth factor binding protein 1., Skelton NJ, Chen YM, Dubree N, Quan C, Jackson DY, Cochran A, Zobel K, Deshayes K, Baca M, Pisabarro MT, Lowman HB, Biochemistry. 2001 Jul 24;40(29):8487-98. PMID:11456486

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