Conformational dynamics of the EGFR kinase domain reveals structural features involved in activation

Abstract

The epidermal growth factor receptor (EGFR) has been the focus of intensive studies because of its importance in cancer research. Thus, a broader understanding of the molecular mechanism of activation of the EGFR kinase will have profound significance for the development of novel therapeutics. Numerous crystal structures of EGFR kinase, including the structure of the activating-kinase dimer, have provided snapshots of the specific pathway. Herein, we performed unrestrained-, as well as targeted-molecular dynamics simulations based on these data, to gain further insight into the conformational changes responsible for activation. Comparison of the monomer- versus activating-EGFR-dimer simulations indicates that the dimerization is stabilizing structural elements associated with the activated state and predicts new salt-bridge interactions involving activation-loop residues that may also be associated with that state. Targeted molecular dynamics simulations of the inactive-to-active EGFR transition, as well as the reverse pathway, confirm the formation of conserved structural features of functional importance for the activity or stabilization of either conformation. Interestingly, simulations of the L834R mutant, which is associated with cancer, suggest that the structural basis of the activation induced by that mutation might be the ability of the mutated R834 residue to consecutively form salt bridges with neighboring acidic residues and cause destabilization of a hydrophobic cluster in the inactive state.