title: Allosteric properties of G protein-coupled receptor oligomers.
abstract: Allosteric regulation of ligand binding is a well-established mechanism regulating the function of G protein-coupled receptors (GPCR). Allosteric modulators have been considered so far as molecules binding to an allosteric site, distinct from that of the reference ligand (orthosteric site), and able to modulate the binding affinity at the orthosteric site and/or the signaling properties resulting from orthosteric site occupancy. Given that most GPCR are known to form dimers or higher order oligomers, we explored whether allosteric interactions could also occur between protomers within oligomeric arrays, thereby influencing binding and signaling receptor properties. Two main conclusions emerged from such studies. First, allosteric modulators can affect one receptor by binding to another receptor within a dimeric or oligomeric complex. Second, allosteric modulators might act on a given receptor by targeting the "orthosteric site" in another receptor of the complex. Allosteric regulation within di(oligo)mers thus implies that the pharmacological properties of a given receptor subtype can be influenced by the array of dimerization partners coexpressed in each particular cell type. Ligands could thus act as agonists or antagonists on 1 receptor, while modulating allosterically the function of a variety of other receptors to which they do not bind directly. Allosteric regulation across GPCR oligomeric interfaces is expected to greatly influence the practice of pharmacology. It will likely affect the design of drug discovery programs, which rely mostly on the overexpression of the receptor of interest in a cell line, thereby focusing on homo-oligomers and ignoring the potential effects of other partners.
authors.affiliation: Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM), Université Libre de Bruxelles, Campus Erasme, 808 Route de Lennik, Elsevier Inc, B-1070, Brussels, Belgium.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Springael
authors.forename: Eneko
authors.initials: E
authors.lastname: Urizar
authors.forename: Sabine
authors.initials: S
authors.lastname: Costagliola
authors.forename: Gilbert
authors.initials: G
authors.lastname: Vassart
authors.forename: Marc
authors.initials: M
authors.lastname: Parmentier
mesh_terms: D000494:Allosteric Regulation; D000495:Allosteric Site; D019281:Dimerization; D016503:Drug Delivery Systems; D015195:Drug Design; D006801:Humans; D008024:Ligands; D011485:Protein Binding; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D008024:Ligands; D043562:Receptors, G-Protein-Coupled