Dimerization arm targeting strategy for inhibition of EGFR.

<p>(a) EGF-induced activation of the extracellular receptor of EGFR. In the inactive state, the dimerization arm (dark blue) of the extracellular receptor is buried within domain IV (beige). In the active state, the receptor undergoes a conformational change to promote intermolecular interactions of the dimerization arm for receptor dimerization. Other features of the receptor include domain I (green), domain II (blue), domain III (brown) and EGF (dark grey). (b) The dimerization arm (dark blue) makes extensive contacts with domain II of the receptor binding partner (beige). (c) Triazolyl-bridged peptides were designed to mimic the dimerization arm, thereby blocking receptor dimerization and activation of the kinase (violet) through occlusion of the dimerization arm binding pocket. Additional features include the transmembrane domain (grey dashed lines). Structures were rendered using PyMol (PDB files: 1NQL, 3NJP, and 2GS6).