Structural basis of the effect of activating mutations on the EGF receptor.
Ioannis GaldadasLuca CarlinoRichard A WardSamantha J HughesShozeb M HaiderFrancesco Luigi GervasioPublished in: eLife (2021)
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.
Keyphrases
- growth factor
- epidermal growth factor receptor
- molecular dynamics simulations
- tyrosine kinase
- advanced non small cell lung cancer
- wild type
- small cell lung cancer
- molecular docking
- structural basis
- molecular dynamics
- induced apoptosis
- protein kinase
- signaling pathway
- cell cycle arrest
- oxidative stress
- endoplasmic reticulum stress
- endothelial cells
- high glucose
- transcription factor
- high resolution
- drug induced
- high speed