Journal article
Oncogenic mutations at the EGFR ectodomain structurally converge to remove a steric hindrance on a kinase-coupled cryptic epitope
L Orellana, AH Thorne, R Lema, J Gustavsson, AD Parisian, A Hospital, TN Cordeiro, P Bernadó, AM Scott, I Brun-Heath, E Lindahl, WK Cavenee, FB Furnari, M Orozco
Proceedings of the National Academy of Sciences of the United States of America | NATL ACAD SCIENCES | Published : 2019
Abstract
Epidermal growth factor receptor (EGFR) signaling is initiated by a large ligand-favored conformational change of the extracellular domain (ECD) from a closed, self-inhibited tethered monomer, to an open untethered state, which exposes a loop required for strong dimerization and activation. In glioblastomas (GBMs), structurally heterogeneous missense and deletion mutations concentrate at the ECD for unclear reasons. We explore the conformational impact of GBM missense mutations, combining elastic network models (ENMs) with multiple molecular dynamics (MD) trajectories. Our simulations reveal that the main missense class, located at the I-II interface away from the self-inhibitory tether, can..
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Funding Acknowledgements
L.O. thanks Dr. K.M. Ferguson for kindly providing 1NQL dimer coordinates. We thank the financial support of the Ministry of Economy and Competitiveness, the Catalan Institution for Research and Advanced Studies, and Generalitat de Catalunya (M.O.); the European Research Council (M.O. and E.L.); the Vetenskapsradet and Swedish e-Science Research Center (E.L.); and the National Brain Tumor Society, NIH Grant R01-NS080939, and James S. McDonnell Foundation (F.B.F.). Calculations were run at the Barcelona Supercomputing Center and Swedish National Infrastructure for Supercomputing, with support by H2020 BioExcel and Elixir-Accelerate. P.B. acknowledges funds from Labex, EpiGenMed, and the "Investissements d'avenir" program (Grant ANR-10-LABX-12-01). L.O. thanks support from the Sven and Lilly Lawskis Foundation, A.H.T. from the National Cancer Institute (Grant 2T32CA009523-29A1), A.D.P. from the NIH (Grant T32GM008666), T.N.C. from MostMicro (Grant LISBOA-01-0145-FEDER-007660), and A.M.S. from the National Health and Medical Research Council (Grant APP1084178). This content is solely the responsibility of the authors and does not necessarily represent the views of the NIH. We acknowledge the use of the European Molecular Biology P12 and the European Synchrotron Radiation Facility Bm29 BioSAXS beamlines.