A Twenty-First Century Cancer Epidemic Caused by Obesity: The Involvement of Insulin, Diabetes, and Insulin-Like Growth Factors
Figure 7
Representation of the crystal structure of the ectodomain of the insulin receptor and model for the interaction of insulin and IGF-1 with their cognate receptors. The three-dimensional structures of a monomer (LHS) and homodimer (RHS) of the insulin receptor isoform B ectodomain are shown (a). Domains are coloured: L1, red; CR, yellow; L2, blue; FnIII-1, green; FnIII-2, cyan; and FnIII-3, magenta. The observed location of the inter-α-chain disulphide at Cys524 is indicated by a (▴) symbol, the chain disulphide at Cys647–Cys860 by a (●) symbol. Images are taken with permission from [312]. The structures of α-chain residues 1–3 (α-chain N-terminus) and 656–719 (ID-α/CT) and of β-chain residues 724–754 (ID-β) and 910–917 (C-terminus of ectodomain) were not solved. The observed termini of the regions of resolved structure within the insert domain of the α-chain and β-chain of the ectodomain monomer are numbered. The insulin receptor ectodomain homodimer is illustrated in its apoconformation, with the twofold symmetry axis indicated by a dashed vertical line ((b), LHS) [85]. The first monomer at the front of the depiction is shown in saturated colour and the second monomer in less intense colour. The thin tubes of the insert domains (ID) indicate their speculative paths. The circled region identified by a blue arrow represents one binding pocket. The region contains the juxtaposition of the residues, derived from L1 of the first monomer and the αCT helix of the second monomer that contribute to binding Site 1 with the residues, derived from the FnIII-1 and FnIII-2 junction of the second monomer that contribute to Site 2. The Site 1 tandem element, formed by the surface of the central β-sheet of L1 of the first insulin receptor monomer and the αCT helix of the second insulin receptor monomer, is shown (RHS). Images are taken with permission from [86]. The proposed location of insulin bound in an insulin receptor binding pocket formed between two insulin receptor monomers with Site 1 from mainly one monomer and Site 2′ from the second monomer of the insulin receptor ectodomain [85, 107, 312] is shown in (c) (LHS). Domains of the receptor are coloured as in (a). Colouring of individual Cα positions within insulin is as follows: residues forming binding Surface 1 of insulin, A1–3, A5, A19, A21, B12, and B16, are shown in purple; residues forming binding Surface 2, A12-13, A17, B13, B17, and B19, are shown in orange; the remaining A-chain residues are in light green and remaining B-chain residues in light blue. Insulin residues B22–B30 are omitted from the model [107]. The proposed location of IGF-1 bound at Site 1 of type I IGF receptor binding pocket is shown (RHS) [313]. The colouring of domains of the type I IGF receptor follows that of the insulin receptor in (a). The backbone of IGF-1 is coloured according to the corresponding colours of the A and B chains of insulin outlined above. The images are taken with permission from [312].
