title: Ligands and signaling proteins govern the conformational landscape explored by a G protein-coupled receptor.
abstract: The dynamic character of G protein-coupled receptors is essential to their function. However, the details of how ligands stabilize a particular conformation to selectively activate a signaling pathway and how signaling proteins affect this conformational repertoire remain unclear. Using a prototypical peptide-activated class A G protein-coupled receptor (GPCR), the ghrelin receptor, reconstituted as a monomer into lipid discs and labeled with a fluorescent conformational reporter, we demonstrate that ligand efficacy and functional selectivity are directly related to different receptor conformations. Of importance, our data bring direct evidence that distinct effector proteins affect the conformational landscape of the ghrelin receptor in different ways. Whereas G proteins affect the balance between active and inactive receptor substates in favor of the active state, agonist-induced arrestin recruitment is accompanied by a marked change in the structural features of the receptor that adopt a conformation different from that observed in the absence of arrestin. In contrast to G proteins and arrestins, μ-AP2 has no significant effect on the organization of the transmembrane core of the receptor. Such a modulation of a GPCR conformational landscape by pharmacologically distinct ligands and effectors provides insights into the structural bases that decisively affect ligand efficacy and subsequent biological responses. This is also likely to have major implications for the design of drugs activating specific GPCR-associated signaling pathways.
authors.affiliation: Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5247, and Université Montpellier 1 et 2, Faculté de Pharmacie, Institut des Biomolécules Max Mousseron, 34093 Montpellier Cedex 05, France. sophie.mary@univ-montp1.fr
authors.forename: Sophie
authors.initials: S
authors.lastname: Mary
authors.forename: Marjorie
authors.initials: M
authors.lastname: Damian
authors.forename: Maxime
authors.initials: M
authors.lastname: Louet
authors.forename: Nicolas
authors.initials: N
authors.lastname: Floquet
authors.forename: Jean-Alain
authors.initials: JA
authors.lastname: Fehrentz
authors.forename: Jacky
authors.initials: J
authors.lastname: Marie
authors.forename: Jean
authors.initials: J
authors.lastname: Martinez
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Banères
mesh_terms: D019393:Arrestin / Q000378:metabolism / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry; D054314:Drug Inverse Agonism; D005453:Fluorescence; D054439:Ghrelin / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D008565:Membrane Proteins / Q000378:metabolism / Q000494:pharmacology; D011487:Protein Conformation; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry / Q000378:metabolism; D054440:Receptors, Ghrelin / Q000819:agonists / Q000737:chemistry* / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013329:Structure-Activity Relationship
chemical_list: D019393:Arrestin; D019086:Bridged Bicyclo Compounds, Heterocyclic; D054439:Ghrelin; D008024:Ligands; D008565:Membrane Proteins; D043562:Receptors, G-Protein-Coupled; D054440:Receptors, Ghrelin; C021149:bimanes; C103903:mu-adaptin-related protein 2