Abstract: The mutation and overexpression of the epidermal growth factor receptor (EGFR) are associated with the development of a variety of cancers, making this prototypical dimerization-activated receptor tyrosine kinase a prominent target of cancer drugs. Using long-timescale molecular dynamics simulations, we find that the wild-type EGFR kinase domain is intrinsically disordered locally and that it becomes ordered only upon dimerization. Our simulations suggest, moreover, that some cancer-linked mutations distal to the dimerization interface, particularly the widespread L834R mutation (also referred to as L858R), facilitate EGFR dimerization by suppressing this local disorder. Corroborating these findings, our biophysical experiments and kinase enzymatic assays indicate that the L834R mutation causes abnormally high activity primarily by promoting EGFR dimerization rather than by allowing activation without dimerization. We also find that phosphorylation of EGFR kinase domain at Tyr845 may suppress the intrinsic disorder, suggesting a molecular mechanism for autonomous EGFR signaling. Additionally, we simulated the binding process of drug molecules binding to EGFR and other protein kinases. Without a priori structural assumption of the binding, these simulations generated the correct binding poses that are virtually identical to those found in crystal structures. Further research is underway to apply such small-molecule binding simulations in drug discovery, particularly in the more challenging discovery of drug molecules that inhibits protein-protein interactions.

Date&Time: December 20, 2013 (Friday), 10:00-11:00 a.m.
Location: 606 Conference Room, No.3 Heqing Road, Haidian District