The three dimensional structure of the type I insulin-like growth factor receptor

Ever since the discovery of insulin and its role in the regulation of gluco se metabolism, there has been great interest in the molecule itself, the in sulin-like growth factors (IGFs), and their receptors (IR and IGF-R). These receptors form a subfamily of tyrosine kinase receptors which are large, t ransmembrane proteins consisting of several structural domains. Their ectod omains have a similar arrangement of two homologous domains (L1 and L2) sep arated by a Cys rich region. The C-terminal half of their ectodomains consi sts of three fibronectin type 3 repeats, and an insert domain that contains the alpha-beta cleavage site. This review summarises the key developments in the understanding of the structure of this family of receptors and their relation to other multidomain proteins. Data presented will include multip le sequence analyses, single molecule electron microscope images of the IGF -1R, insulin receptor (IR), and IR-Fab complexes, and the three dimensional structure of the first three domains of the IGF-1R determined to 2.6 Angst rom resolution by x ray crystallography. The L domains each adopt a compact shape consisting of a single stranded, right handed beta -helix. The Cys r ich region is composed of eight disulphide bonded modules, seven of which f orm a rod shaped domain with modules associated in an unusual manner.