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Molecular Pharmacology

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Research ArticleArticle

Identification of Determinants of Glucose-Dependent Insulinotropic Polypeptide Receptor That Interact with N-Terminal Biologically Active Region of the Natural Ligand

Tahir Yaqub, Irina G. Tikhonova, Jens Lättig, Remi Magnan, Marie Laval, Chantal Escrieut, Cyril Boulègue, Chandralal Hewage and Daniel Fourmy
Molecular Pharmacology April 2010, 77 (4) 547-558; DOI: https://doi.org/10.1124/mol.109.060111
Tahir Yaqub
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Irina G. Tikhonova
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Jens Lättig
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Remi Magnan
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Marie Laval
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Chantal Escrieut
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Cyril Boulègue
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Chandralal Hewage
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Daniel Fourmy
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Abstract

Glucose-dependent insulinotropic polypeptide receptor (GIPR), a member of family B of the G-protein coupled receptors, is a potential therapeutic target for which discovery of nonpeptide ligands is highly desirable. Structure-activity relationship studies indicated that the N-terminal part of glucose-dependent insulinotropic polypeptide (GIP) is crucial for biological activity. Here, we aimed at identification of residues in the GIPR involved in functional interaction with N-terminal moiety of GIP. A homology model of the transmembrane core of GIPR was constructed, whereas a three-dimensional model of the complex formed between GIP and the N-terminal extracellular domain of GIPR was taken from the crystal structure. The latter complex was docked to the transmembrane domains of GIPR, allowing in silico identification of putative residues of the agonist binding/activation site. All mutants were expressed at the surface of human embryonic kidney 293 cells as indicated by flow cytometry and confocal microscopy analysis of fluorescent GIP binding. Mutation of residues Arg183, Arg190, Arg300, and Phe357 caused shifts of 76-, 71-, 42-, and 16-fold in the potency to induce cAMP formation, respectively. Further characterization of these mutants, including tests with alanine-substituted GIP analogs, were in agreement with interaction of Glu3 in GIP with Arg183 in GIPR. Furthermore, they strongly supported a binding mode of GIP to GIPR in which the N-terminal moiety of GIP was sited within transmembrane helices (TMH) 2, 3, 5, and 6 with biologically crucial Tyr1 interacting with Gln224 (TMH3), Arg300 (TMH5), and Phe357 (TMH6). These data represent an important step toward understanding activation of GIPR by GIP, which should facilitate the rational design of therapeutic agents.

Footnotes

    fn-5
  • This research was supported in part by Association pour la Recherche sur le Cancer [Grant 4870]; and by the Fondation pour la Recherche Médicale (to J.L.).

  • fn-6
  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.109.060111.

  • fn-7
  • ABBREVIATIONS:

    GIP
    glucose-dependent insulinotropic polypeptide (gastric inhibitory polypeptide)
    GIPR
    glucose-dependent insulinotropic polypeptide receptor
    GPCR
    G protein-coupled receptor
    GL
    glucagon
    SCT
    secretin
    VIP
    vasoactive intestinal peptide
    PTH
    parathyroid hormone
    ECD
    extracellular domain (ectodomain)
    ECL2
    extracellular loop 2
    TMH
    transmembrane helix
    HEK
    human embryonic kidney
    PCR
    polymerase chain reaction
    DMEM
    Dulbecco's modified Eagle's medium
    D-PBS
    Dulbecco's phosphate buffered saline
    HPLC
    high-performance liquid chromatography.

    • Received August 6, 2009.
    • Accepted January 8, 2010.
  • Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 77 (4)
Molecular Pharmacology
Vol. 77, Issue 4
1 Apr 2010
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Research ArticleArticle

Identification of Determinants of Glucose-Dependent Insulinotropic Polypeptide Receptor That Interact with N-Terminal Biologically Active Region of the Natural Ligand

Tahir Yaqub, Irina G. Tikhonova, Jens Lättig, Remi Magnan, Marie Laval, Chantal Escrieut, Cyril Boulègue, Chandralal Hewage and Daniel Fourmy
Molecular Pharmacology April 1, 2010, 77 (4) 547-558; DOI: https://doi.org/10.1124/mol.109.060111

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Research ArticleArticle

Identification of Determinants of Glucose-Dependent Insulinotropic Polypeptide Receptor That Interact with N-Terminal Biologically Active Region of the Natural Ligand

Tahir Yaqub, Irina G. Tikhonova, Jens Lättig, Remi Magnan, Marie Laval, Chantal Escrieut, Cyril Boulègue, Chandralal Hewage and Daniel Fourmy
Molecular Pharmacology April 1, 2010, 77 (4) 547-558; DOI: https://doi.org/10.1124/mol.109.060111
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