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J. Biol. Chem., Vol. 280, Issue 23, 22198-22204, June 10, 2005

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Evidence That Interspecies Polymorphism in the Human and Rat Cholecystokinin Receptor-2 Affects Structure of the Binding Site for the Endogenous Agonist Cholecystokinin^*

Ingrid Langer¶, Irina G. Tikhonova, Marie-Agnès Travers, Elodie Archer-Lahlou, Chantal Escrieut, Bernard Maigret||, and Daniel Fourmy**

From the Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Louis Bugnard, CHU Rangueil, 31432 Toulouse Cedex 4, France and ^||Laboratoire de Chimie Théorique, Université de Nancy, 54506 Vandoeuvre, Nancy, France

The cholecystokinin (CCK) receptor-2 exerts very important central and peripheral functions by binding the neuropeptides cholecystokinin or gastrin. Because this receptor is a potential therapeutic target, great interest has been devoted to the identification of efficient antagonists. However, interspecies genetic polymorphism that does not alter cholecystokinin-induced signaling was shown to markedly affect activity of synthetic ligands. In this context, precise structural study of the agonist binding site on the human cholecystokinin receptor-2 is a prerequisite to elucidating the molecular basis for its activation and to optimizing properties of synthetic ligands. In this study, using site-directed mutagenesis and molecular modeling, we delineated the binding site for CCK on the human cholecystokinin receptor-2 by mutating amino acids corresponding to that of the rat homolog. By doing so, we demonstrated that, although resembling that of rat homolog, the human cholecystokinin receptor-2 binding site also displays important distinct structural features that were demonstrated by susceptibility to several point mutations (F120A, Y189A, H207A). Furthermore, docking of CCK in the human and rat cholecystokinin receptor-2, followed by dynamic simulations, allowed us to propose a plausible structural explanation of the experimentally observed difference between rat and human cholecystokinin-2 receptors.

Received for publication, February 16, 2005 , and in revised form, April 1, 2005.

^* This work was supported in part by a grant from Association pour la Recherche contre le Cancer ARC 4430 and 3282. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Recipients of a fellowship from Fondation pour la Recherche Médicale.

^¶ Present address: Faculté de Médecine-Université Libre de Bruxelles, Laboratoire Chimie Biologique, 808 Route de Lennik CP611, B-1070 Brussels, Belgium.

^** To whom correspondence should be addressed: Institut Frédératif de Recherche 31, Institut Louis Bugnard, BP 84225, Unité 531, 31432 Toulouse cedex 4, France. E-mail: fourmyd{at}toulouse.inserm.fr.

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This article has been cited by other articles:

				M. Foucaud, E. Marco, C. Escrieut, C. Low, B. Kalindjian, and D. Fourmy Linking Non-peptide Ligand Binding Mode to Activity at the Human Cholecystokinin-2 Receptor J. Biol. Chem., December 19, 2008; 283(51): 35860 - 35868. [Abstract] [Full Text] [PDF]

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				M. Dufresne, C. Seva, and D. Fourmy Cholecystokinin and gastrin receptors. Physiol Rev, July 1, 2006; 86(3): 805 - 847. [Abstract] [Full Text] [PDF]

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