Expanding the Concept of G Protein-Coupled Receptor (GPCR) Dimer Asymmetry towards GPCR-Interacting Proteins.docVIP

Pharmaceuticals 2011, 4, 273-284; doi:10.3390/ph4020273 OPEN ACCESS pharmaceuticals ISSN 1424-8247 /journal/pharmaceuticals Review Expanding the Concept of G Protein-Coupled Receptor (GPCR) Dimer Asymmetry towards GPCR-Interacting Proteins Maud Kamal 1,2, Pascal Maurice 1,2 and Ralf Jockers 1,2, * 1 Institut Cochin, Universite Paris Descartes, CNRS, Paris, France Inserm, U1016, Paris, France; E-Mails: maud.kamal@inserm.fr (M.K.); pascal.maurice@inserm.fr (P.M.) 2 * Author to whom correspondence should be addressed; E-Mail: ralf.jockers@inserm.fr; Tel.: +331-40-51-64-34; Fax: +331-40-51-64-30. Received: 6 December 2010; in revised form: 7 January 2011 / Accepted: 14 January 2011 / Published: 25 January 2011 Abstract: G protein-coupled receptors (GPCRs), major targets of drug discovery, are organized in dimeric and/or oligomeric clusters. The minimal oligomeric unit, the dimer, is composed of two protomers, which can behave differently within the dimer. Several examples of GPCR asymmetry within dimers at the level of ligand binding, ligand- promoted conformational changes, conformational changes within transmembrane domains, G protein coupling, and most recently GPCR-interacting proteins (GIPs), have been reported in the literature. Asymmetric organization of GPCR dimers has important implications on GPCR function and drug design. Indeed, the extension of the “asymmetry concept” to GIPs adds a new level of specific therapeutic intervention. Keywords: GPCR; dimerization; GIP; allosterism 1. Introduction A growing body of pharmacological, biochemical and biophysical data indicate that GPCRs form functional homo- and hetero-dimers and most likely higher-order oligomers [1,2]. Formation of such oligomeric structures has been shown to provide shielding from the quality-control checkpoints during the biosynthetic pathway [3] and to have an important role in modulating GPCR function and signalin