Ligand binding and dynamics of the monomeric epidermal growth factor receptor ectodomain
Article first published online: 18 AUG 2013
Copyright © 2013 The Authors. Proteins published by Wiley Periodicals, Inc.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Proteins: Structure, Function, and Bioinformatics
Volume 81, Issue 11, pages 1931–1943, November 2013
How to Cite
Loeffler, H. H. and Winn, M. D. (2013), Ligand binding and dynamics of the monomeric epidermal growth factor receptor ectodomain. Proteins, 81: 1931–1943. doi: 10.1002/prot.24339
- Issue published online: 16 OCT 2013
- Article first published online: 18 AUG 2013
- Accepted manuscript online: 12 JUN 2013 05:27PM EST
- Manuscript Accepted: 19 MAY 2013
- Manuscript Revised: 26 APR 2013
- Manuscript Received: 29 JAN 2013
- UK Biotechnology and Biological Sciences Research Council. Grant Number: BB/G006911/1
- molecular dynamics;
- free energy;
- molecular mechanics Poisson–Boltzmann surface area;
- extracellular domain;
The ectodomain of the human epidermal growth factor receptor (hEGFR) controls input to several cell signalling networks via binding with extracellular growth factors. To gain insight into the dynamics and ligand binding of the ectodomain, the hEGFR monomer was subjected to molecular dynamics simulation. The monomer was found to be substantially more flexible than the ectodomain dimer studied previously. Simulations where the endogeneous ligand EGF binds to either Subdomain I or Subdomain III, or where hEGFR is unbound, show significant differences in dynamics. The molecular mechanics Poisson–Boltzmann surface area method has been used to derive relative free energies of ligand binding, and we find that the ligand is capable of binding either subdomain with a slight preference for III. Alanine-scanning calculations for the effect of selected ligand mutants on binding reproduce the trends of affinity measurements. Taken together, these results emphasize the possible role of the ectodomain monomer in the initial step of ligand binding, and add details to the static picture obtained from crystal structures. Proteins 2013; 81:1931–1943. © 2013 The Authors. Proteins published by Wiley Periodicals, Inc.