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.
Highlights
A growing body of pharmacological, biochemical and biophysical data indicate that G protein-coupled receptors (GPCRs) form functional homo- and hetero-dimers and most likely higher-order oligomers [1,2]
In the absence of G protein coupling, no such asymmetric conformational changes were observed [15]. These results suggest that the interaction of the G protein with the receptor dimer would bring specific constraints, which prevent a symmetric functioning of the dimer and that the G protein itself might be partly responsible for the asymmetric functioning in a context where ligand binding cis-activates G protein binding to the same protomer [14]
Asymmetric behavior of GPCR dimers is further supported by observations at the level of ligand binding and ligand-promoted conformational changes within the heptahelical transmembrane domain as discussed in the paragraphs
Summary
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 signaling [4]. Intercommunication among the different protomers results in dimer asymmetry and asymmetric recruitment of GPCR-interacting proteins (GIPs) including heterotrimeric G proteins. This mini-review summarizes the evidence supporting the emerging concept of asymmetric behavior within a GPCR complex. We will briefly discuss asymmetry in G protein coupling, ligand binding, conformational changes within transmembrane domains, and binding of GIPs
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