Membrane receptors : structure, dynamics and pathology
par- 21 novembre 2012
Membrane receptors : structure, dynamics and pathologies
Our work id focused on the study of arginine-vasopressin (AVP) and oxytocin (OT) receptors, belonging to the G protein-coupled receptors (GPCR) family. We investigate their structure and functioning, dynamics of the interactions with their protein partners, and the links between these receptors and pathologies. This scientific program is dedicated to increase our knowledge in the field of transmembrane heptahelical receptors and their associated signaling pathways, and to develop new potential therapeutic molecules. We have been involved in the cloning of AVP/OT receptors, in their pharmacological and G protein coupling characterization, in the development of peptidic and nonpeptidic selective agonists and antagonists and in the design of radiolabeled and fluorescent analogues of these ligands. We also published one of the first tridimensional (3D) models of a peptidic hormone interacting with its GPCR (indeed, AVP with the V1a receptor) and experimentally identified receptor domains or single residues responsible for ligand binding, affinity, or selectivity. Our expertise in the expression and handling of these receptors constitute a strong basis to the projects we have been developing for the past few years. During the last decade, our understanding of the structure and the functioning of GPCR has rapidly evolved and many new concepts have now to be taken into account. For instance, the constitutive activity of receptors, the discovery of inverse agonists, allosteric regulators and functionally-selective ligands, the role of receptor dimerization, the identification of new interacting proteins and consequently new signalling pathways, the existence of receptor conformational state-dependent "signalosomes" are of crucial importance. In this context, the family of AVP/OT receptors is a model system allowing to approach most of these scientific questions and to better understand the activation mechanism and the structure of Class A GPCR as well as to discover new associated signaling molecules.
Recent publications :
Rahmeh R, Damian M, Cottet M, Orcel H, Mendre C, Durroux T, Sharma KS, Durand G, Pucci B, Trinquet E, Zwier JM, Deupi X, Bron P, Banères JL, Mouillac B, Granier S. (2012). Structural insights into biased G protein-coupled receptor signaling revealed by fluorescence spectroscopy. Proc Natl Acad Sci. 109(17), 6733-8.
Banères JL, Popot JL, Mouillac B. (2011) New advances in production and functional folding of G-protein-coupled receptors. Trends Biotechnol. 29(7), 314-22.
Albizu L, Cottet M, Kralikova M, Stoev S, Seyer R, Brabet I, Roux T, Bazin H, Bourrier E, Lamarque L, Breton C, Rives ML, Newman A, Javitch J, Trinquet E, Manning M, Pin JP, Mouillac B, Durroux T. (2010) Time-resolved FRET between GPCR ligands reveals oligomers in native tissues. Nat. Chem. Biol. 6(8), 587-94.
Laure Arcemisbehere, Tuhinadri Sen, Laure Boudier, Marie-Noelle Balestre, Gerald Gaibelet, Emilie Detouillon, Helene Orcel, Christiane Mendre, Rita Rahmeh, Sebastien Granier, Corinne Vives, Franck Fieschi, Marjorie Damian, Thierry Durroux, Jean-Louis Banères and Bernard Mouillac (2010) Leukotriene BLT2 receptor monomers activate the Gi2 GTP-binding protein more efficiently than dimers. J Biol Chem, 285(9), 6337-47.
Jean-Alphonse F, Perkovska S, Frantz M, Durroux T, Méjean C, Morin D, Loison S, Bonnet D, Hibert M, Mouillac B, Mendre C (2009) Biased agonists of the arginine-vasopressin V2 receptor : novel pharmacochaperones with therapeutic potential for treating congenital nephrogenic diabetes insipidus. J Am Soc Nephrol. 20(10) : 2190-2203.