✍ Scribed by Alpeshkumar K. Malde; Sudha S. Srivastava; Evans C. Coutinho
No coin nor oath required. For personal study only.
Gastric inhibitory polypeptide (GIP, or glucose‐dependent insulinotropic polypeptide) is a 42‐amino acid incretin hormone moderating glucose‐induced insulin secretion. Antidiabetic therapy based on GIP holds great promise because of the fact that its insulinotropic action is highly dependent on the level of glucose, overcoming the sideeffects of hypoglycemia associated with the current therapy of Type 2 diabetes. The truncated peptide, GIP(1–30)NH~2~, has the same activity as the full length native peptide. We have studied the structure of GIP(1–30)NH~2~ and built a model of its G‐protein coupled receptor (GPCR). The structure of GIP(1–30)NH~2~ in DMSO‐d~6~ and H~2~O has been studied using 2D NMR (total correlation spectroscopy (TOCSY), nuclear overhauser effect spectroscopy (NOESY), double quantum filtered‐COSY (DQF‐COSY), ^13^C‐heteronuclear single quantum correlation (HSQC) experiments, and its conformation built by MD simulations with the NMR data as constraints. The peptide in DMSO‐d~6~ exhibits an α‐helix between residues Ile12 and Lys30 with a discontinuity at residues Gln19 and Gln20. In H~2~O, the α‐helix starts at Ile7, breaks off at Gln19, and then continues right through to Lys30. GIP(1–30)NH~2~ has all the structural features of peptides belonging to family B1 GPCRs, which are characterized by a coil at the N‐terminal and a long C‐terminal α‐helix with or without a break. A model of the seven transmembrane (TM) helices of the GIP receptor (GIPR) has been built on the principles of comparative protein modeling, using the crystal structure of bovine rhodopsin as a template. The N‐terminal domain of GIPR has been constructed from the NMR structure of the N‐terminal of corticoptropin releasing factor receptor (CRFR), a family B1 GCPR. The intra and extra cellular loops and the C‐terminal have been modeled from fragments retrieved from the PDB. On the basis of the experimental data available for some members of family B1 GPCRs, four pairs of constraints between GIP(1–30)NH~2~ and its receptor were used in the FTDOCK program, to build the complete model of the GIP(1–30)NH~2~ : GIPR complex. The model can rationalize the various experimental observations including the potency of the truncated GIP peptide. This work is the first complete model at the atomic level of GIP(1–30)NH~2~ and of the complex with its GPCR. Copyright © 2007 European Peptide Society and John Wiley & Sons, Ltd.
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