An Allosteric Mechanism for Activation of the Kinase Domain of Epidermal Growth Factor Receptor

摘要: The mechanism by which the epidermal growth factor receptor (EGFR) is activated upon dimerization has eluded definition. We find that EGFR kinase domain can be increasing its local concentration or mutating a leucine (L834R) in activation loop, phosphorylation of not required for activation. This suggests intrinsically autoinhibited, and an intermolecular interaction promotes Using further mutational analysis crystallography we demonstrate autoinhibited conformation resembles Src cyclin-dependent kinases (CDKs). results from formation asymmetric dimer C-terminal lobe one plays role analogous to cyclin CDK/cyclin complexes. CDK/cyclin-like complex formed two domains thus explains EGFR-family receptors homo- heterodimerization.