Understanding interactions of gastric inhibitory polypeptide (GIP) with its G-protein coupled receptor through NMR and molecular modeling

Malde, Alpeshkumar K., Srivastava, Sudha S. and Coutinho, Evans C. (2007) Understanding interactions of gastric inhibitory polypeptide (GIP) with its G-protein coupled receptor through NMR and molecular modeling. Journal of Peptide Science, 13 5: 287-300. doi:10.1002/psc.839


Author Malde, Alpeshkumar K.
Srivastava, Sudha S.
Coutinho, Evans C.
Title Understanding interactions of gastric inhibitory polypeptide (GIP) with its G-protein coupled receptor through NMR and molecular modeling
Journal name Journal of Peptide Science   Check publisher's open access policy
ISSN 1099-1387
1075-2617
Publication date 2007-01-01
Sub-type Article (original research)
DOI 10.1002/psc.839
Volume 13
Issue 5
Start page 287
End page 300
Total pages 14
Place of publication Chichester, West Sussex, UK
Publisher John Wiley & Sons
Language eng
Subject 030402 Biomolecular Modelling and Design
030406 Proteins and Peptides
Abstract 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)NH2, has the same activity as the full length native peptide. We have studied the structure of GIP(1-30)NH2 and built a model of its G-protein coupled receptor (GPCR). The structure of GIP(1-30)NH2 in DMSO-d6 and H2O has been studied using 2D NMR (total correlation spectroscopy (TOCSY), nuclear overhauser effect spectroscopy (NOESY), double quantum filtered-COSY (DQF-COSY), 13C-heteronuclear single quantum correlation (HSQC) experiments, and its conformation built by MD simulations with the NMR data as constraints. The peptide in DMSO-d6 exhibits an -helix between residues Ile12 and Lys30 with a discontinuity at residues Gln19 and Gln20. In H2O, the -helix starts at Ile7, breaks off at Gln19, and then continues right through to Lys30. GIP(1-30)NH2 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 -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)NH2 and its receptor were used in the FTDOCK program, to build the complete model of the GIP(1-30)NH2 : 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)NH2 and of the complex with its GPCR. Copyright © 2007 European Peptide Society and John Wiley & Sons, Ltd.
Keyword diabetes
gastric inhibitory polypeptide (GIP)
GIP(1-30)NH2
GIP receptor (GIPR)
2D NMR
G-protein coupled receptor (GPCR)
homology modeling
FTDOCK
MD simulations
Q-Index Code C1

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
School of Chemistry and Molecular Biosciences
 
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