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Mapping the Binding Site of Arginine Vasopressin to V_1a and V_1b Vasopressin Receptors

Bioinformatics of the Drug (J.R., D.R.), Centre Nationale de la Recherche Scientifique-Université Louis Pasteur (CNRS-ULP), Unité Mixte de Recherche (UMR) 7175-LC1, F-67401 Illkirch, France; and Institut de Génomique Fonctionnelle (A.P., B.M., M.T., T.D., G.G.), CNRS UMR 5203, Institut National de la Santé et de la Recherche Médicale Unité 661, Universités Montpellier I et II, F-34094 Montpellier Cédex 5, France

Address all correspondence and request for reprints to: Dr. Didier Rognan, Centre Nationale de la Recherche Scientifique Université Louis Pasteur Unité Mixte de Recherche 7175-LC1, 74 Route du Rhin, F-67401 Illkirch, France. E-mail: didier.rognan{at}pharma.u-strasbg.fr.

Starting from the 2.8-Å resolution x-ray structure of bovine rhodopsin, three-dimensional molecular models of the complexes between arginine vasopressin and two receptor subtypes (V_1a, V_1b) have been built. Amino acid sequence alignment and docking studies suggest that four key residues (1.35, 2.65, 4.61, and 5.35) fine tune the binding of vasopressin and related peptide agonists to both receptor subtypes. To validate these predictions, a series of single or double mutants were engineered at V_1a and V_1b receptor subtypes and tested for their binding and functional properties. Two negatively charged amino acids at positions 1.35 and 2.65 are key anchoring residues to the Arg8 residue of arginine vasopressin. Moreover, two amino acids (V^4.61 and P^5.35) delineating a hydrophobic subsite at the human V_1b receptor are responsible for the recognition of V_1b selective peptide agonists. Last, one of the latter positions (5.35) is hypothesized to explain the pharmacological species differences between rat and human vasopressin receptors for a V_1b peptide agonist. Altogether these refined three-dimensional models of V_1a and V_1b human receptors should enable the identification of further new selective V_1a and V_1b agonists as pharmacological but also therapeutic tools.

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