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Structural biology of insulin and IGF1 receptors: implications for drug design

Structural biology of insulin and IGF1 receptors: implications for drug design The cloning of the complementary DNAs and genes for the insulin and insulin-like growth factor 1 (IGF1) receptors, as well as tertiary-structure predictions, have provided valuable insights into the overall domain organization of the receptors. No crystal structure of the insulin- or IGF1-receptor complexes with their ligands is yet available, but crystal structures of the large domain 1 (L1)–Cys-rich (CR)–L2 amino-terminal fragment of the IGF1 receptor, and of the insulin- and IFG1-receptor tyrosine-kinase domains both in the inactive and activated conformation, are available. Single-molecule electron-microscopic imaging of the insulin receptor has given some indications of the overall organization of the extracellular receptor domains, although there have been variable results and a tendency in some cases to over-interpret low-resolution data. Knowledge of the structure of several receptor tyrosine-kinase domains has led to attempts to screen for, or design, mimetics or inhibitors, with some degree of success. Agonists or antagonists that target the ligand-binding sites might have a greater chance to be selective, hence the importance of understanding the nature of the ligand-binding mechanism. Mapping the ligand-binding sites on the insulin and IGF1 receptors by receptor crosslinking with photoreactve ligands, by examining the binding selectivity of chimeric insulin–IGF1 receptors, by alanine-scanning mutagenesis of receptor domains and by reconstitution of minimized receptor constructs with low or high affinity, has provided a wealth of information on the binding epitopes. Likewise, mapping of the residues on the insulin molecule that are involved in receptor binding has progressed, and has revealed the existence of a second binding surface in addition to the so-called 'classical' binding surface. The information on IGF1 and IGF2 is more fragmentary. Alternative crosslinking models that explain the complex ligand-binding kinetics of the insulin and IGF1 receptors (including negative cooperativity) are discussed. Various strategies for designing agonists or antagonists of a dimerizing receptor are discussed, building on the experience acquired with the erythropoietin receptor. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Nature Reviews Drug Discovery Springer Journals

Structural biology of insulin and IGF1 receptors: implications for drug design

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References (170)

Publisher
Springer Journals
Copyright
Copyright © 2002 by Nature Publishing Group
Subject
Biomedicine; Biomedicine, general; Pharmacology/Toxicology; Biotechnology; Medicinal Chemistry; Molecular Medicine; Cancer Research
ISSN
1474-1776
eISSN
1474-1784
DOI
10.1038/nrd917
Publisher site
See Article on Publisher Site

Abstract

The cloning of the complementary DNAs and genes for the insulin and insulin-like growth factor 1 (IGF1) receptors, as well as tertiary-structure predictions, have provided valuable insights into the overall domain organization of the receptors. No crystal structure of the insulin- or IGF1-receptor complexes with their ligands is yet available, but crystal structures of the large domain 1 (L1)–Cys-rich (CR)–L2 amino-terminal fragment of the IGF1 receptor, and of the insulin- and IFG1-receptor tyrosine-kinase domains both in the inactive and activated conformation, are available. Single-molecule electron-microscopic imaging of the insulin receptor has given some indications of the overall organization of the extracellular receptor domains, although there have been variable results and a tendency in some cases to over-interpret low-resolution data. Knowledge of the structure of several receptor tyrosine-kinase domains has led to attempts to screen for, or design, mimetics or inhibitors, with some degree of success. Agonists or antagonists that target the ligand-binding sites might have a greater chance to be selective, hence the importance of understanding the nature of the ligand-binding mechanism. Mapping the ligand-binding sites on the insulin and IGF1 receptors by receptor crosslinking with photoreactve ligands, by examining the binding selectivity of chimeric insulin–IGF1 receptors, by alanine-scanning mutagenesis of receptor domains and by reconstitution of minimized receptor constructs with low or high affinity, has provided a wealth of information on the binding epitopes. Likewise, mapping of the residues on the insulin molecule that are involved in receptor binding has progressed, and has revealed the existence of a second binding surface in addition to the so-called 'classical' binding surface. The information on IGF1 and IGF2 is more fragmentary. Alternative crosslinking models that explain the complex ligand-binding kinetics of the insulin and IGF1 receptors (including negative cooperativity) are discussed. Various strategies for designing agonists or antagonists of a dimerizing receptor are discussed, building on the experience acquired with the erythropoietin receptor.

Journal

Nature Reviews Drug Discovery – Springer Journals

Published: Oct 1, 2002

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