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

Autor:	Galdadas I; Department of Chemistry, University College London, London, United Kingdom.; Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, Geneva, Switzerland., Carlino L; Oncology R&D, AstraZeneca, Cambridge, United Kingdom., Ward RA; Oncology R&D, AstraZeneca, Cambridge, United Kingdom., Hughes SJ; Oncology R&D, AstraZeneca, Cambridge, United Kingdom., Haider S; UCL School of Pharmacy, University College London, London, United Kingdom., Gervasio FL; Department of Chemistry, University College London, London, United Kingdom.; Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, Geneva, Switzerland.; Institute of Structural and Molecular Biology, University College London, London, United Kingdom.; Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2021 Jul 28; Vol. 10. Date of Electronic Publication: 2021 Jul 28.
DOI:	10.7554/eLife.65824
Abstrakt:	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. Competing Interests: IG, SH, FG No competing interests declared, LC, RW, SH is affiliated with AstraZeneca. The author has no financial interests to declare. (© 2021, Galdadas et al.)
Databáze:	MEDLINE
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