期刊
CELL
卷 167, 期 5, 页码 1241-+出版社
CELL PRESS
DOI: 10.1016/j.cell.2016.10.038
关键词
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资金
- Netherlands Organization for Scientific Research (NWO) [700.26.121, 700.10.443, STW12152]
- VIDI [723.013.008]
- iNEXT [653706]
- Horizon 2020 program of the European Union
- project Proteins At Work [184.032.201]
- program of the Netherlands Proteomics Centre - NWO, National Roadmap Largescale Research Facilities of the Netherlands
- uNMR-NL, an NWO
The epidermal growth factor receptor (EGFR) represents one of the most common target proteins in anti-cancer therapy. Todirectly 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 ligandbinding favors the cooperative binding required for receptor dimerization, causing allosteric activation of the intracellular tyrosine kinase.
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