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Structure and Dynamics of the EGF Receptor as Revealed by Experiments and Simulations and Its Relevance to Non-Small Cell Lung Cancer

1
Central Laser Facility, Research Complex at Harwell, STFC Rutherford Appleton Laboratory, Harwell Oxford, Didcot, Oxford OX11 0QX, UK
2
Department of Chemistry, University College London, London WC1H 0AJ, UK
*
Authors to whom correspondence should be addressed.
Cells 2019, 8(4), 316; https://doi.org/10.3390/cells8040316
Received: 6 March 2019 / Revised: 29 March 2019 / Accepted: 30 March 2019 / Published: 5 April 2019
(This article belongs to the Special Issue Receptor Tyrosine Kinases in Health and Disease)
The epidermal growth factor receptor (EGFR) is historically the prototypical receptor tyrosine kinase, being the first cloned and the first where the importance of ligand-induced dimer activation was ascertained. However, many years of structure determination has shown that EGFR is not completely understood. One challenge is that the many structure fragments stored at the PDB only provide a partial view because full-length proteins are flexible entities and dynamics play a key role in their functionality. Another challenge is the shortage of high-resolution data on functionally important higher-order complexes. Still, the interest in the structure/function relationships of EGFR remains unabated because of the crucial role played by oncogenic EGFR mutants in driving non-small cell lung cancer (NSCLC). Despite targeted therapies against EGFR setting a milestone in the treatment of this disease, ubiquitous drug resistance inevitably emerges after one year or so of treatment. The magnitude of the challenge has inspired novel strategies. Among these, the combination of multi-disciplinary experiments and molecular dynamic (MD) simulations have been pivotal in revealing the basic nature of EGFR monomers, dimers and multimers, and the structure-function relationships that underpin the mechanisms by which EGFR dysregulation contributes to the onset of NSCLC and resistance to treatment. View Full-Text
Keywords: EGFR; lung cancer; receptor signaling; structure; MD simulations EGFR; lung cancer; receptor signaling; structure; MD simulations
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Martin-Fernandez, M.L.; Clarke, D.T.; Roberts, S.K.; Zanetti-Domingues, L.C.; Gervasio, F.L. Structure and Dynamics of the EGF Receptor as Revealed by Experiments and Simulations and Its Relevance to Non-Small Cell Lung Cancer. Cells 2019, 8, 316.

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