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

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. [Display omitted] •NMR can be applied to study activation of full-length EGFR in native membranes•Solid-state NMR provides insight into structure and mobility of full-length EGFR•Data identify conformational selection as a key factor for receptor activation An NMR approach shows how receptors move in native membranes at high resolution, revealing that, while the intracellular domain of EGFR is rigid, the extracellular domain is highly dynamic until bound by ligand.