The quaternary structure of G protein‐coupled receptors

Abstract

G protein-coupled receptors (GPCRs) are seven-transmembrane-helix polypeptides that are encoded by somewhere in the region of 3% of the genes of mammalian genomes and are the most actively targeted class of polypeptides for small molecule drug design. Despite this, and observations scattered throughout the literature for a number of years suggesting that GPCRs can exist as dimers or higher-order oligomers, it is only in the last five years that analysis of the structural organization of GPCRs has become wide-ranging. Although a number of key issues, including the molecular basis of dimerization ⁄oligomerization, the importance of dimerization ⁄oligomerization for function, and the physiological occurrence and relevance of hetero-dimers containing GPCRs produced by two different genes, remain both contentious and central research themes, there is now little doubt that dimerization ⁄oligomerization does occur. The four minireviews in this issue of FEBS Journal address different aspects of GPCR dimerization ⁄oligomerization. In the first of these Michel Bouvier and I discuss, and address critically, the approaches that have and are being employed to examine GPCR dimerization ⁄ oligomerization. Given the large number of studies that are being performed in this area and the limitations of each individual technique we conclude that concurrent application of a range of approaches that employ distinct techniques is required to provide convincing data. At the current time experimental information on the mechanisms of dimerization and the interfaces involved is both limited and fragmentary. Indeed, models for dimerization include both ‘linear packing’ models in which the external faces of specific transmembrane helices provide the interface and ‘domain swap’ models in which the two elements of the dimer exchange transmembrane segments. Informatics can suggest plausible mechanisms and in the second article Marta Filizola and Harel Weinstein consider the contributions that informatic studies have made to this field and the manner in which iterative cycles of informatic analysis and direct experiments may lead to clearer understanding. The third article by Roberto Maggio and colleagues focuses on the development of distinct pharmacology and function associated with GPCR hetero-dimer formation. As noted above, there is considerable interest in the possibility that at least a proportion of GPCR ‘hetero-dimers’ represent ‘domain swaps’. In such a situation it is almost axiomatic that differences in the details of ligand binding would be produced in comparison with ‘linear packing’ dimers. The extent of existence of GPCR hetero-dimers in physiological settings remains to be established but if they are relatively common they may represent a novel and currently unappreciated set of drug targets for the pharmaceutical industry. Although the first three articles all concentrate on members of the rhodopsin-like (or family A) GPCRs because numerically these are by far the largest group, the first clear example of GPCR hetero-dimerization and its importance for function came from the family C GPCRs. These all contain a long N-terminal extracellular domain in which the natural ligands bind within a ‘venus flytrap’ structure. Crystal structures of such domains in both empty and ligand-bound arrangements have provided detailed insights into conformational reorganization of such GPCR dimers in the presence of ligands. The ability to create chimeric family C GPCRs by combining the extracellular domain of one with the transmembrane and intracellular element of a second has also provided dramatic insights into the importance of dimerization for function, and in the final article in the series Jean-Phillipe Pin and colleagues discuss such studies and the development of allosteric modulators of function of family C GPCRs, another area with major implications for the development of novel classes of small molecule therapeutics.