Characterization of a comparative model of the extracellular domain of theepidermal growth factor receptor

The Epidermal Growth Factor (EGF) receptor is a tyrosine kinase that mediat es the biological effects of ligands such as EGF and transforming growth fa ctor alpha. An understanding of the molecular basis of its action has been hindered by a lack of structural and mutational data on the receptor. We ha ve 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 third doma ins of the EGF receptor, L1 and L2, are right-handed beta helices. The seco nd and fourth domains of the EGF receptor, S1 and S2, consist of the module s held together by disulfide bonds, which, except for the first module of t he Si domain, form rod-like structures. The arrangement of the LI and S1 do mains 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 significantl y different. Using the EGF receptor model and limited information from the literature, we have proposed a number of regions that may be involved in th e functioning of the receptor. In particular, the faces containing the larg e beta sheets in the L1 and L2 domains have been suggested to be involved w ith ligand binding of EGF to its receptor.