Oncogenic mutations counteract intrinsic disorder in the EGFR kinase and promote receptor dimerization

摘要: The mutation and overexpression of the epidermal growth factor receptor (EGFR) are associated with development a variety cancers, making this prototypical dimerization-activated tyrosine kinase prominent target cancer drugs. Using long-timescale molecular dynamics simulations, we find that N lobe dimerization interface wild-type EGFR domain is intrinsically disordered it becomes ordered only upon dimerization. Our simulations suggest, moreover, some cancer-linked mutations distal to interface, particularly widespread L834R (also referred as L858R), facilitate by suppressing local disorder. Corroborating these findings, our biophysical experiments enzymatic assays indicate causes abnormally high activity primarily promoting rather than allowing activation without We also phosphorylation at Tyr845 may suppress intrinsic disorder, suggesting mechanism for autonomous signaling.