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Cell. 2016 Nov 17;167(5):1241-1251.e11. doi: 10.1016/j.cell.2016.10.038. Epub 2016 Nov 10.

EGFR Dynamics Change during Activation in Native Membranes as Revealed by NMR.

Author information

1
NMR Spectroscopy, Bijvoet Center for Biomolecular Research, Utrecht University, 3584 CH Utrecht, the Netherlands.
2
Cell Biology, Department of Biology, Faculty of Science, Utrecht University, 3584 CH Utrecht, the Netherlands.
3
Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CH Utrecht, the Netherlands.
4
Biomolecular Imaging, Bijvoet Center for Biomolecular Research, Utrecht University, 3584 CH Utrecht, the Netherlands.
5
Cell Biology, Department of Biology, Faculty of Science, Utrecht University, 3584 CH Utrecht, the Netherlands. Electronic address: p.vanbergen@uu.nl.
6
NMR Spectroscopy, Bijvoet Center for Biomolecular Research, Utrecht University, 3584 CH Utrecht, the Netherlands. Electronic address: m.baldus@uu.nl.

Abstract

The epidermal growth factor receptor (EGFR) represents one of the most common target proteins in anti-cancer therapy. To directly examine the structural and dynamical properties of EGFR activation by the epidermal growth factor (EGF) in native membranes, we have developed a solid-state nuclear magnetic resonance (ssNMR)-based approach supported by dynamic nuclear polarization (DNP). In contrast to previous crystallographic results, our experiments show that the ligand-free state of the extracellular domain (ECD) is highly dynamic, while the intracellular kinase domain (KD) is rigid. Ligand binding restricts the overall and local motion of EGFR domains, including the ECD and the C-terminal region. We propose that the reduction in conformational entropy of the ECD by ligand binding favors the cooperative binding required for receptor dimerization, causing allosteric activation of the intracellular tyrosine kinase.

KEYWORDS:

EGFR; NMR; Solid-state NMR; activation; cancer; membrane protein; receptor; tyrosine kinase

PMID:
27839865
DOI:
10.1016/j.cell.2016.10.038
[Indexed for MEDLINE]
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