Characterization of a comparative model of the extracellular domain of the epidermal growth factor receptor.

Jorissen R.N., Epa V.C., Treutlein H.R., Garrett, T.P.J., Ward, C.W., and Burgess A.W.,

Protein Science 9(2): 322-336. 2000

Abstract: The Epidermal Growth Factor (EGF) receptor is a tyrosine kinase that mediates the biological effects of ligands such as EGF and transforming growth factor alpha . An understanding of the molecuar basis of its action has been hindered by a lack of structural and mutational data on the receptor. We have constructed comparative models of the four extracellular domains of the EGF receptor that are based on the structure of the first three domains of the insulin-like growth factor-1 (IGF-1) receptor. The first and second domains of the EGF receptor, S1 and S2, consist of the modules held together by disulfide bonds, which, except for the first modules of the S1 domain, form rod-like structures. The arrangement of the L1 and S1 domains of the model are similar to that of the first two domains of the IGF-1 receptor, whereas that of the L2 and S2 domains appear to be significantly different. Using the EGF receptor model and limited information from the literature, we have proposed a number of regions that may be involved in the functioning of the receptor. In particular, the faces containing the large beta sheets in the L1 and L2 domains have been suggested to be suggested to be involvled with ligand binding of EGF to its receptor.

Keywords: comparative modeling; epidermal growth factor

Coordinates: Model structures of the EGF receptor L1-S1 domains and the L2-S2 domains are available from the Protein Databank with PDB codes: 1dnq and 1dnr respectively.

Local copies of the models: L1 and S1 domains and L2 and S2 domains of the EGF receptor ectodomain. Note that coloring by temperature factor colors each model by a "confidence" value for each of the residue's mainchain coordinates. Right click on the links to save locally.

Generation of additional MODELLER Calpha-Calpha restraints:

  1. Use Homology module of InsightII to build coordinates for target protein from template, but only for those residues you wish to have additional restraints for (e.g. underlined residues of figure 1 in the EGFR ECD article). Save the coordinates.
  2. Create an alignment with of the partial structure built in 1 with the full sequence of the target protein. For an example, click here. This example is for the construction of restraints for the L1 adn S1 domains of the EGF receptor.
  3. Execute MODELLER with a script similar to this example.

PUBMED ID: 10716183