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Updated: Jul 13, 2026

Deciphering the Structural Effects of Activating EGFR Somatic Mutations with Molecular Dynamics Simulation
Published on: May 20, 2020
Ligand-induced structural transitions in ErbB receptor extracellular domains
Jessica P Dawson1, Zimei Bu, Mark A Lemmon
1Department of Biochemistry & Biophysics, University of Pennsylvania School of Medicine, 422 Curie Boulevard, Philadelphia, PA 19104, USA.
Abstract:
Crystallographic studies showed that epidermal growth factor (EGF) receptor activation involves major domain rearrangements. Without bound ligand, the extracellular region of the receptor (sEGFR) adopts a "tethered" configuration with its dimerization site occluded by apparently autoinhibitory intramolecular interactions. Ligand binding causes the receptor to become "extended," breaking the tether and exposing the dimerization site. Using small-angle X-ray scattering (SAXS), we confirm that the tethered and extended conformations are also adopted in solution, and we describe low-resolution molecular envelopes for an intact sEGFR dimer. We also use SAXS to monitor directly the transition from a tethered to extended configuration in the monomeric extracellular regions of ErbB3 and a dimerization-defective EGFR mutant. Finally, we show that mutating every intramolecular tether interaction in sEGFR does not greatly alter its conformation. These findings explain why tether mutants fail to activate EGF receptor and provide new insight into regulation of ErbB receptor conformation.
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