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J. Biol. Chem., Vol. 276, Issue 44, 41100-41111, November 2, 2001

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Control of Conformational Equilibria in the Human B₂ Bradykinin Receptor
MODELING OF NONPEPTIDIC LIGAND ACTION AND COMPARISON TO THE RHODOPSIN STRUCTURE^*

Jacky Marie, Eric Richard, Didier Pruneau^§, Jean-Luc Paquet^§, Christian Siatka, Renée Larguier, Cecilia Poncé, Philippe Vassault, Thierry Groblewski^¶, Bernard Maigret, and Jean-Claude Bonnafous^**

From  INSERM U439, 70 rue de Navacelles 34090 Montpellier, the ^§ Laboratoires Fournier, 50 rue de Dijon, and  Laboratoire de Chimie théorique, Université de Nancy 1, 54506 Vandoeuvre-les-Nancy Cédex, 21121 Daix

A prototypic study of the molecular mechanisms of activation or inactivation of peptide hormone G protein-coupled receptors was carried out on the human B₂ bradykinin receptor. A detailed pharmacological analysis of receptor mutants possessing either increased constitutive activity or impaired activation or ligand recognition allowed us to propose key residues participating in intramolecular interaction networks stabilizing receptor inactive or active conformations: Asn¹¹³ and Tyr¹¹⁵ (TM III), Trp²⁵⁶ and Phe²⁵⁹ (TM VI), Tyr²⁹⁵ (TM VII) which are homologous of the rhodopsin residues Gly¹²⁰, Glu¹²², Trp²⁶⁵, Tyr²⁶⁸, and Lys²⁹⁶, respectively. An essential experimental finding was the spatial proximity between Asn¹¹³, which is the cornerstone of inactive conformations, and Trp²⁵⁶ which plays a subtle role in controlling the balance between active and inactive conformations. Molecular modeling and mutagenesis data showed that Trp²⁵⁶ and Tyr²⁹⁵ constitute, together with Gln²⁸⁸, receptor contact points with original nonpeptidic ligands. It provided an explanation for the ligand inverse agonist behavior on the WT receptor, with underlying restricted motions of TMs III, VI, and VII, and its agonist behavior on the Ala¹¹³ and Phe²⁵⁶ constitutively activated mutants. These data on the B₂ receptor emphasize that conformational equilibria are controlled in a coordinated fashion by key residues which are located at strategic positions for several G protein-coupled receptors. They are discussed in comparison with the recently determined rhodopsin crystallographic structure.

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