How insulin and IGF-1 bind to their receptors
The available crystal structure of the insulin receptor extracellular domain (1) and that of the L1-CR-L2 N-terminal domain of the IGF-I receptor (2) unfortunately do not contain the bound ligand.
However, a wealth of information on the mechanism of ligand binding to the insulin and IGF-I receptors has been gathered from a variety of biochemical approaches (for review see 3-6), including studies of the kinetics of radioligand binding (8), photoaffinity crosslinking of ligands to the receptors (9-12), and alanine (or other amino acids) scanning mutagenesis of both the ligands (4, 12-14) and receptors (15-18).
From these studies plausible models have emerged (8, 19). The De Meyts 1994 bivalent crosslinking binding model (8, Fig. 1) was supported by the recent crystal structure of the insulin receptor (1) and by mathematical modelling (20,21), explaining the complex ligand binding kinetics of the insulin and IGF-I receptors which exhibit negative cooperativity, whereby the binding of a second ligand molecule weakens the binding of the first bound molecule by accelerating its dissociation from the receptor.
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