The available crystal structure of the insulin receptor extracellular domain and that of the L1-CR-L2 N-terminal domain of the IGF-I receptor, 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 was gathered from various biochemical approaches.
These approaches include studies of the kinetics of radioligand binding, photoaffinity cross-linking of ligands to the receptors, and alanine (or other amino acids) scanning mutagenesis of both the ligands and receptors.
From these studies, plausible models have emerged. The De Meyts 1994 bivalent cross-linking binding model was supported by the recent crystal structure and mathematical modelling of the insulin receptor. These models explain the complex ligand binding kinetics of the insulin and IGF-I receptors that exhibit negative cooperativity. 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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