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A model for the three-dimensional structure of insulin-like growth factor (IGF) is proposed based on the close sequence homology of IGF with insulin, the tertiary structure of which is known. The IGF molecule is postulated to have an insulin-like main chain conformation for residues equivalent to B6-B27 and A1-A21 and a hydrophobic core nearly identical to that of insulin. A short connecting peptide of twelve residues and an extension at the COOH-terminus are easily accommodated on the molecular surface. MATERIALS AND METHODS The model was built in several stages. The proposed structure was first constructed using Lapquip model parts at a scale of 1 cm = 1 A. This was examined for unfavorable intramolecular contracts and readjusted before the coordinates of each atom were read off using a mechanical device. The approximate coordinates were then regularized using the "modelfit" computer program of Isaacs et al (12), and bond lengths and angles and other intramolecular distances were calculated using an IBM 360/65 computer. The model was then displayed on a computer graphics system (Digital Equipment Corp. graphics with a PDPll computer) using programs written by D. Richardson, P. Pauling, and C. Chothia, and adjustments were made using the interactive facilities of the graphics system to optimize the intramolecular distances. Finally, the model was regeometricized using "modelfit" and stereo pairs of the model were generated in hard copy. RESULTS AND DISCUSSIONThree-dimensional model for IGF I Table 1 shows the sequences of human IGF I, IGF II, and porcine insulin aligned so that the maximum homology is obtained. The numbering for the insulin A and B chains is indicated, as is the numbering for the IGF I polypeptide. The sequence of the IGF connecting peptide of 12 residues is also included, but because this shows no homology with the proinsulin connecting peptide, the latter is omitted. IGF I has an extension of eight residues at the COOH terminus of the A chain. Table 2 gives the differences in numbers of amino acids between the 51 amino acids of porcine insulin and the equivalent residues of other insulins, the protein hormone relaxin (13)(14)(15), which also appears to be homologous with insulin, and IGF.The sequence comparison shows a close homology for residues 5-25 of IGF (B6-B26 of insulin) and 42-61 (A1-A20). The arrangement of cystines is identical in IGF and insulin, and glycines 7 (B8), 19 (B20), and 22 (B23), which have dihedral angles that are disallowed for residues with side chains, are conserved, so that the polypeptide backbone can assume the same three-dimensional structure as insulin. We began by building the sequence 5-26 and 42-61 into an insulin-like structure. This conformation is shown schematically in Fig. 1. Residues 8-18 (B9-B19) and [43][44][45][46][47][48] (A2-A7) are right-handed a-helices and residues 54-60 (A13-A19) formed a less organized right-handed helix. Cys 47 and 52 (A6 and All) and Cys 61 and 18 (A20 and B19) have their disulfides placed in the core, while the Cys ...

The growing realization that biologically active polypeptides can be grouped in families, the members of which show structural and functional relatedness, is illustrated by the four families which are represented in the pancreas by the hormones insulin, glucagon, somatostatin and pancreatic polypeptide.