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Molecular Pharmacology

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Research ArticleArticle

Identification of Tyrosine 189 and Asparagine 358 of the Cholecystokinin 2 Receptor in Direct Interaction with the Crucial C-Terminal Amide of Cholecystokinin by Molecular Modeling, Site-Directed Mutagenesis, and Structure/Affinity Studies

Céline Galés, Marc Poirot, Julien Taillefer, Bernard Maigret, Jean Martinez, Luis Moroder, Chantal Escrieut, Lucien Pradayrol, Daniel Fourmy and Sandrine Silvente-Poirot
Molecular Pharmacology May 2003, 63 (5) 973-982; DOI: https://doi.org/10.1124/mol.63.5.973
Céline Galés
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Marc Poirot
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Julien Taillefer
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Bernard Maigret
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Jean Martinez
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Luis Moroder
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Chantal Escrieut
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Lucien Pradayrol
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Daniel Fourmy
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Sandrine Silvente-Poirot
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Abstract

The cholecystokinin (CCK) receptors CCK1R and CCK2R exert important central and peripheral functions by binding the neuropeptide cholecystokinin. Because these receptors are potential therapeutic targets, great interest has been devoted to the identification of efficient ligands that selectively activate or inhibit these receptors. A complete mapping of the CCK binding site in these receptors would help to design new CCK ligands and to optimize their properties. In this view, a molecular model of the CCK2R occupied by CCK was built to identify CCK2R residues that interact with CCK functional groups. No such study has yet been reported for the CCK2R. Docking of CCK in the receptor was performed by taking into account our previous mutagenesis data and by using, as constraint, the direct interaction that we demonstrated between His207 in the CCK2R and Asp8 of CCK (Mol Pharmacol54:364–371, 1998; J Biol Chem274:23191–23197, 1999). Two residues that had not been revealed in our previous mutagenesis studies, Tyr189 (Y4.60) and Asn358 (N6.55), were identified in interaction via hydrogen bonds with the C-terminal amide of CCK, a crucial functional group of the peptide. Mutagenesis of Tyr189 (Y4.60) and Asn358 (N6.55) as well as structure-affinity studies with modified CCK analogs validated these interactions and the involvement of both residues in the CCK binding site. These results indicate that the present molecular model is an important tool to identify direct contact points between CCK and the CCK2R and to rapidly progress in mapping of the CCK2R binding site. Moreover, comparison of the present CCK2R.CCK molecular model with that of CCK1R.CCK, which we have previously published and validated, clearly argues that the positioning of CCK in these receptors is different.

Footnotes

  • This work was supported in part by a grant from the Association pour la recherche sur le cancer (ARC 5481).

  • Abbreviations:
    CCK
    cholecystokinin
    CCK1R
    cholecystokinin 1 receptor
    CCK2R
    cholecystokinin 2 receptor
    DMEM
    Dulbecco's modified Eagle's medium
    BSA
    bovine serum albumin
    TM. transmembrane
    IP, inositol phosphate
    PLC
    phospholipase C
    GPCR
    G protein-coupled receptor
    • Received July 22, 2002.
    • Accepted January 17, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 63 (5)
Molecular Pharmacology
Vol. 63, Issue 5
1 May 2003
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Research ArticleArticle

Identification of Tyrosine 189 and Asparagine 358 of the Cholecystokinin 2 Receptor in Direct Interaction with the Crucial C-Terminal Amide of Cholecystokinin by Molecular Modeling, Site-Directed Mutagenesis, and Structure/Affinity Studies

Céline Galés, Marc Poirot, Julien Taillefer, Bernard Maigret, Jean Martinez, Luis Moroder, Chantal Escrieut, Lucien Pradayrol, Daniel Fourmy and Sandrine Silvente-Poirot
Molecular Pharmacology May 1, 2003, 63 (5) 973-982; DOI: https://doi.org/10.1124/mol.63.5.973

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Research ArticleArticle

Identification of Tyrosine 189 and Asparagine 358 of the Cholecystokinin 2 Receptor in Direct Interaction with the Crucial C-Terminal Amide of Cholecystokinin by Molecular Modeling, Site-Directed Mutagenesis, and Structure/Affinity Studies

Céline Galés, Marc Poirot, Julien Taillefer, Bernard Maigret, Jean Martinez, Luis Moroder, Chantal Escrieut, Lucien Pradayrol, Daniel Fourmy and Sandrine Silvente-Poirot
Molecular Pharmacology May 1, 2003, 63 (5) 973-982; DOI: https://doi.org/10.1124/mol.63.5.973
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