Structural basis of the effect of activating mutations on the EGF receptor

Mutations within the kinase domain of epidermal growth factor receptor (EGFR) are common oncogenic driver events in non-small cell lung cancer. Although activation EGFR normal cells is primarily driven by growth-factor-binding-induced dimerization, mutations on different exons have been found to affect equilibrium between its active and inactive conformations giving rise growth-factor-independent activation. Using molecular dynamics simulations combined with enhanced sampling techniques, we compare here conformational landscape monomers homodimers wild-type mutated forms ?ELREA L858R, as well two exon 20 insertions, D770-N771insNPG, A763-Y764insFQEA. The differences energy landscapes consistent multiple mechanisms action including regulation hinge motion, stabilization dimeric interface, local unfolding transitions. Overall, a combination effects caused leads observed aberrant signaling.