Structure and Machanism-Base Design of ErbB Receptor Inhibitors
Annual rept. 1 Sep 2004-31 Aug 2005
JOHNS HOPKINS UNIV BALTIMORE MD
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The work proposed for this award involved using the crystal structures of the extracellular domains of the EGF receptor EGFR and its homologs HER2NeuErbB2, HER3ErbB3, and HER4ErbB4, which were recently determined in my lab and elsewhere, to design a new class of inhibitors of this family of receptors. These structures had shown that ligands bind to two separate surfaces in these receptors that are normally far apart in the absence of ligand. Binding ligand e.g. EGF requires a large conformational change in the receptor to bring these surfaces close together, and it is this conformational change that then leads to receptor dimerization and initiation of a signaling cascade through activation of a cytoplasmic tyrosine kinase. Our idea had been to create through mutagenesis a ligand that bound more tightly to one of the binding surfaces but not to the other. Theoretically, this ligand would bind to the receptor but not induce the conformational change needed to activate the receptor and thus serve an inhibitor of the receptor.
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