Structural relationships between the insulin receptor and epidermal growth factor receptor families and other proteins.

The insulin receptor (IR) and epidermal growth factor receptor (EGFR) families are closely related members of the receptor tyrosine kinase superfamily, and are among the more intensively studied proteins in biology. Deregulated signaling by the type-1 insulin-like growth factor receptor (IGF-1R) or members of the EGFR family has been implicated in the progression of a variety of cancers. These receptors have thus emerged as validated therapeutic targets for the development of antitumor agents. In this review, recent progress in the elucidation of the three-dimensional structures of the extracellular domains of both receptor families is discussed. While the IGF-1R provided the first description of the extracellular domains of these two receptor families, it is the EGFR family in which greatest progress has been achieved. Over the past year, the field has progressed from having a complete absence of X-ray crystal structures to having eight such structures; ErbB-2 alone or complexed with the two monoclonal antibodies pertuzumab (Genentech Inc/Roche Holdings AG/Chugai Pharmaceutical Co Ltd) and trastuzamab, ErbB-3 without a ligand, EGFR with a ligand bound in an unactivated monomeric conformation, and EGFR with either epidermal growth factor (EGF) or transforming growth factor-alpha (TGFalpha) in a 2:2 dimeric complex. This review will discuss these developments and the opportunities they provide for the design of new therapeutic agents targeting their extracellular domains.