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Molecualr modelling techniques can be used to make predictions about the structures of proteins where experimental structural information is not available. Prior to the recent solution of structures of the ligand-bound ectodomain and tyrosine kinase of the EGF receptor, we constructed models of these parts of the EGF receptor.

The model of the EGF receptor ectodomain was used to assist the construction of a mutagenesis experiment on the receptor and also the interpretation of results. An amino acid important for EGF binding was identified and supported our prediction of one of the ligand binding sites on the EGF receptor. We then used the model to predict the mode of binding of EGF to the major ligand binding domain EGF receptor.

The newly solved structure of the ligand-bound EGF receptor ectodomain fragment and the entire ectodomain of ErbB3 allow our predictions to be evaluated. Using the newly solved structure, we are performing molecular dynamics simulations to assess which regions of the EGF receptor are flexible and also to look for correlated motions.

Models of the L1 and S1 domains (right) and L2 and S2 domains (left) of the EGF receptor, as superimposed on the experimentally determined structure of the IGF-1 receptor L1, cysteine-rich and L2 domains (not shown). The IGF-1 receptor was the structural template from which the EGF receptor model was constructed.

People involved in the research.

• Robert Jorissen
• Tony Burgess

Collaborators involved in the research.

• Colin Ward, Vidana Epa (CSIRO)
• Tom Garrett, Jonathon Baell (WEHI)

Publications:
Modeling the epidermal growth factor -- epidermal growth factor receptor L2 domain interaction: implications for the ligand binding process.
Jorissen RN, Treutlein HR, Epa VC, Burgess AW.
J Biomol Struct Dyn. 19: 961-972 (2002). [Medline entry]

Identification of a determinant of epidermal growth factor receptor ligand-binding specificity using a truncated, high-affinity form of the ectodomain.
Elleman TC, Domagala T, McKern NM, Nerrie M, Lonnqvist B, Adams TE, Lewis J, Lovrecz GO, Hoyne PA, Richards KM, Howlett GJ, Rothacker J, Jorissen RN, Lou M, Garrett TPJ, Burgess AW, Nice EC, Ward CW.
Biochemistry. 2001 Jul 31;40(30):8930-9. [Medline entry]

Characterization of a model of a comparative model of the extracellular domain of the epidermal growth factor receptor.
Jorissen RN, Epa VC, Treutlein HR, Garrett TPJ, Ward CW, Burgess AW.
Protein Science 9: 322-336 (2000). [Medline entry]

A model for the activation of the epidermal growth factor receptor kinase involvement of an asymmetric dimer?
Groenen LC, Walker F, Burgess AW, Treutlein HR.
Biochemistry. 1997 Apr 1;36(13):3826-36. [Medline entry]