Solution structure of human insulin-like growth factor II. Relationship to receptor and binding protein interactions.
The three-dimensional structure of human insulin-like growth factor (IGF) II in aqueous solution at pH 3.1 and 300 K has been determined from nuclear magnetic resonance data and restrained molecular dynamics calculations. Structural constraints consisting of 502 NOE-derived distance constraints, 11 dihedral angle restraints, and three disulfide bridges were used as input for distance geometry calculations in DIANA and X-PLOR, followed by simulated annealing refinement and energy minimization in X-PLOR. The resulting family of 20 structures was well defined in the regions of residues 5 to 28 and 41 to 62, with an average pairwise root-mean-square deviation of 1.24 A for the backbone heavy-atoms (N, C2, C) and 1.90 A for all heavy atoms. The poorly defined regions consist of the N and C termini, part of the B-domain, and the C-domain loop. Resonances from these regions of the protein gave stronger cross peaks in two dimensional NMR spectra, consistent with significant motional averaging. The main secondary structure elements in IGF-II are alpha-helices encompassing residues 11 to 21, 42 to 49 and 53 to 59. A small anti-parallel beta-sheet is formed by residues 59 to 61 and 25 to 27, while residues 26 to 28 appear to participate in intermolecular beta-sheet formation. The structure of IGF-II in the well-defined regions is very similar to those of the corresponding regions of insulin and IGF-I. Significant differences between IGF-II and IGF-I occur near the start of the third helix, in a region known to modulate affinity for the type 2 IGF receptor, and at the C terminus. The IGF II structure is discussed in relation to its binding sites for the insulin and IGF receptors and the IGF binding proteins.
Torres
A M
AM
NMR Laboratory Biomolecular Research Institute, Parkville, Australia.
Forbes
B E
BE
Aplin
S E
SE
Wallace
J C
JC
Francis
G L
GL
Norton
R S
RS
D000595:Amino Acid Sequence; D003198:Computer Simulation; D006801:Humans; D007328:Insulin / Q000737:chemistry; D007334:Insulin-Like Growth Factor I / Q000737:chemistry; D007335:Insulin-Like Growth Factor II / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D017527:Receptor, IGF Type 2 / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry; D012984:Software; D012996:Solutions
D007328:Insulin; D017527:Receptor, IGF Type 2; D011994:Recombinant Proteins; D012996:Solutions; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II