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

• DOI: 10.7554/elife.65824
• Publication Date: 2021-07-06T12:03:38Z
• Authors: Ioannis Galdadas; Luca Carlino; Richard A Ward; Samantha J Hughes; Shozeb Haider; Francesco Luigi G...
• Keywords: Simulations; Lung Neoplasms; none; QH301-705.5; Science; Cancer biology; Intercellular Signaling Peptides and Proteins / genetics; Molecular dynamics; Molecular Dynamics Simulation; Computational biology; 03 medical and health sciences; computational biology; ErbB Receptors / metabolism; info:eu-repo/classification/ddc/615; Carcinoma, Non-Small-Cell Lung; None; Carcinoma, Non-Small-Cell Lung / genetics; Humans; human; Biology (General); cancer biology; Cancer Biology; Lung Neoplasms / genetics; 0303 health sciences; computational; Computational; In silico; Q; R; systems biology; mutations; molecular dynamics; 3. Good health; ErbB Receptors; in silico; Mutation; Medicine; Intercellular Signaling Peptides and Proteins; simulations; Systems biology; ErbB Receptors / genetics; Mutations; Human; Protein Binding

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