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J Biol Chem, Vol. 274, Issue 29, 20457-20464, July 16, 1999

Arginine 336 and Asparagine 333 of the Human Cholecystokinin-A Receptor Binding Site Interact with the Penultimate Aspartic Acid and the C-terminal Amide of Cholecystokinin

Véronique Gigoux, Chantal Escrieut, Jean-Alain Fehrentz^§, Sandrine Poirot, Bernard Maigret^¶, Luis Moroder, Danielle Gully^**, Jean Martinez^§, Nicole Vaysse, and Daniel Fourmy

From  INSERM U151, Institut Louis Bugnard, Centre Hospitalier Universitaire Rangueil, Bat. L3, 31403 Toulouse Cedex 4, France, the ^¶ Laboratoire de Chimie Théorique, Université de Nancy, 54506 Vandoeuvre les Nancy, ^§ CNRS UMR 5810, Faculté de Pharmacie, 34060 Montpellier, France, the  Max-Planck-Institut für Biochemie, 82143 Martinsried, Germany, and ^** Sanofi-Recherche, 195 route d'Espagne, 31036 Toulouse Cedex, France

The cholecystokinin-A receptor (CCK-AR) is a G protein-coupled receptor that mediates important central and peripheral cholecystokinin actions. Residues of the CCK-AR binding site that interact with the C-terminal part of CCK that is endowed with biological activity are still unknown. Here we report on the identification of Arg-336 and Asn-333 of CCK-AR, which interact with the Asp-8 carboxylate and the C-terminal amide of CCK-9, respectively. Identification of the two amino acids was achieved by dynamics-based docking of CCK in a refined three-dimensional model of CCK-AR using, as constraints, previous results that demonstrated that Trp-39/Gln-40 and Met-195/Arg-197 interact with the N terminus and the sulfated tyrosine of CCK, respectively. Arg-336-Asp-8 and Asn-333-amide interactions were pharmacologically assessed by mutational exchange of Arg-336 and Asn-333 in the receptor or reciprocal elimination of the partner chemical functions in CCK. This study also allowed us to demonstrate that (i) the identified interactions are crucial for stabilizing the high affinity phospholipase C-coupled state of the CCK-AR·CCK complex, (ii) Arg-336 and Asn-333 are directly involved in interactions with nonpeptide antagonists SR-27,897 and L-364,718, and (iii) Arg-336 but not Asn-333 is directly involved in the binding of the peptide antagonist JMV 179 and the peptide partial agonist JMV 180. These data will be used to obtain an integrated dynamic view of the molecular processes that link agonist binding to receptor activation.

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