Biochemistry 36, 3826-3836, 1997
Abstract: The binding of epidermal growth factor (EGF) to its receptor leads to receptor dimerisation, which activates the intracellular kinase domain. Homology models of the inactive and active forms of the EGF-receptor kinase domains have been derived and these models suggest that the active form can be stabilised by the interaction of helix C and the surrounding area in one receptor monomer with one of two possible complementary surfaces on a second receptor monomer. Both hydrophobic interaction sites are strongly conserved within the EGF-receptor family but not in other tyrosine kinases. Two of the three predicted kinase dimers are symmetric, the other is asymmetric and is predicted to contain only one active kinase. One of the symmetric models and the asymmetric model would account for the effects of two mutations in helix C (Y740F and V741G) on kinase activity. They also provide an explanation for previously reported dominant negative mutants of the EGF-receptor, and have interesting implications for the signalling through homo- and heterodimers of the family members: EGF-receptor, erbB2, erbB3 and erbB4.
The coordinates of the models presented in this paper can be downloaded below. You can either request the full models including the solvent, or a much smaller file of the model without hydrogen atoms and solvent water molecules (but with the water molecules from the templates). Note: to save to disk you may need to right click on the links.
Fig. 4a. Active form of the EGFR kinase (full model (0.7Mb), kinase only(0.17Mb))
Fig. 4b. Inactive form of the EGFR kinase (full model (0.7Mb), kinase only (0.17Mb))
Fig. 7a. Symmetric dimer of two active EGFR kinase domains (full model (1.4Mb), kinase domains only (0.34Mb))
Fig. 7b. Symmetric dimer of two active EGFR kinase domains (full model (1.4Mb), kinase domains only(0.34Mb))
Fig. 7c. Asymmetric dimer of one active and one inactive EGFR kinase domain (full model (1.4Mb), kinase domains only(0.34Mb))
PUBMED ID: 9092812