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J. Biol. Chem., Vol. 283, Issue 51, 35860-35868, December 19, 2008

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Linking Non-peptide Ligand Binding Mode to Activity at the Human Cholecystokinin-2 Receptor^*

Magali Foucaud¹, Esther Marco¹, Chantal Escrieut, Caroline Low, Barret Kalindjian, and Daniel Fourmy²

From the INSERM, Unit 858, Toulouse and Université de Toulouse 3, Toulouse, France and the James Black Foundation, 68 Half Moon Lane, Dulwich, London, SE24 9JE, United Kingdom

Given the importance of G-protein-coupled receptors as pharmacological targets in medicine, efforts directed at the understanding the molecular mechanism by which pharmacological compounds regulate their activity is of paramount importance. Here, we investigated at an atomic level the mechanism of inverse agonism and partial agonism of two high affinity, high selectivity very similar non-peptide ligands of the cholecystokinin-2 receptor (CCK2R) which differ by the absence or presence of a methyl group on their indole moiety. Using in silico, site-directed mutagenesis and pharmacological experiments, we demonstrated that these functionally different activities are due to differing anchoring modes of the two compounds to a residue of helix II (Thr-2.61) in the inactive state of the CCK2R. The binding mode of the inverse agonist allows the ligand to interact through its phenyl moiety with a key amino acid for CCK2R activation (Trp-6.48), preventing rotation of helix VI and, thus, CCK2R activation, whereas the partial agonist binds deeper into the binding pocket and closer to helix V, so that CCK2R activation is favored. This study on the molecular mechanism of ligand action opens the possibility of target-based optimization of G protein-coupled receptor non-peptide ligands.

Received for publication, July 18, 2008 , and in revised form, October 6, 2008.

^* 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 These authors contributed equally.

² To whom correspondence should be addressed: INSERM U858, I2MR-équipe 13, 1, Avenue Jean Poulhès, BP 84225, 31432 Toulouse cedex 4. E-mail: fourmyd{at}inserm.fr.

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