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J. Biol. Chem., Vol. 282, Issue 39, 28779-28790, September 28, 2007

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Mechanism of Activation of a G Protein-coupled Receptor, the Human Cholecystokinin-2 Receptor^*

From the INSERM, Unit 858, Institut Fédératif de Recherche, 31432 Toulouse, France and the Université de Toulouse 3, 31062 Toulouse, France

G protein-coupled receptors (GPCRs) represent a major focus in functional genomics programs and drug development research, but their important potential as drug targets contrasts with the still limited data available concerning their activation mechanism. Here, we investigated the activation mechanism of the cholecystokinin-2 receptor (CCK2R). The three-dimensional structure of inactive CCK2R was homology-modeled on the basis of crystal coordinates of inactive rhodopsin. Starting from the inactive CCK2R modeled structure, active CCK2R (namely cholecystokinin-occupied CCK2R) was modeled by means of steered molecular dynamics in a lipid bilayer and by using available data from other GPCRs, including rhodopsin. By comparing the modeled structures of the inactive and active CCK2R, we identified changes in the relative position of helices and networks of interacting residues, which were expected to stabilize either the active or inactive states of CCK2R. Using targeted molecular dynamics simulations capable of converting CCK2R from the inactive to the active state, we delineated structural changes at the atomic level. The activation mechanism involved significant movements of helices VI and V, a slight movement of helices IV and VII, and changes in the position of critical residues within or near the binding site. The mutation of key amino acids yielded inactive or constitutively active CCK2R mutants, supporting this proposed mechanism. Such progress in the refinement of the CCK2R binding site structure and in knowledge of CCK2R activation mechanisms will enable target-based optimization of nonpeptide ligands.

Received for publication, January 12, 2007 , and in revised form, June 21, 2007.

^* This work was supported in part by Association pour la Recherche contre le Cancer Grants ARC 3282 and 3756. 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.

¹ Supported by fellowships from the "Fondation pour la Recherche Medicale."

² These two authors contributed equally to this work.

³ "Chargée de Recherches" from the Fonds National de la Recherche Scientifique, Belgium.

⁴ To whom correspondence should be addressed: IFR 31, Institut Louis Bugnard, BP 84225, Unité 858, 31432 Toulouse cedex 4, France. E-mail: fourmyd{at}toulouse.inserm.fr.

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