Allosteric regulation of epidermal growth factor (EGF) receptor ligand binding by tyrosine kinase inhibitors
Abstract
The epidermal growth factor (EGF) receptor is a classical receptor tyrosine kinase with an extracellular ligand-binding domain and an intracellular kinase domain. Mutations in the EGF receptor have been shown to drive uncontrolled cell growth and are associated with a number of different tumors. Two different types of ATP-competitive EGF receptor tyrosine kinase inhibitors have been identified that bind to either the active (type I) or inactive (type II) conformation of the kinase domain. Despite the fact that both types of inhibitors block tyrosine kinase activity, they exhibit differential efficacies in different tumor types. Here, we show that in addition to inhibiting kinase activity, these inhibitors allosterically modulate ligand binding. Our data suggest that the conformations of the EGF receptor extracellular domain and intracellular kinase domain are coupled and that these conformations exist in equilibrium. Allosteric regulators, such as the small-molecule tyrosine kinase inhibitors, as well as mutations in the EGF receptor itself, shift the conformational equilibrium among the active and inactive species, leading to changes in EGF receptor-binding affinity. Our studies also reveal unexpected positive cooperativity be...Continue Reading
References
Crystal structure of the complex of human epidermal growth factor and receptor extracellular domains
Complex relationship between ligand binding and dimerization in the epidermal growth factor receptor
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