G Protein-Coupled Receptors: Finding Common Threads

RESEARCH HIGHLIGHTS

Nature Reviews Drug Discovery | AOP, published online 15 February 2013; doi:10.1038/nrd3959

G PROTEIN-COUPLED RECEPTORS

GETTY Finding common threads

Despite substantial recent advances in the understanding of the structure and function of G protein-coupled receptors (GPCRs), many of these so the authors next receptors remain poorly character- performed a virtual between the ized. Now, two papers seek to help screen to prospectively seven α-helices that address such gaps by organizing identify candidates. For one such are conserved across the GPCRs based on either ligand or Together, pair of neighbouring recep- structures (for both active and structural similarities. these tors — κ-opioid receptor (OPRK) inactive states). They suggest that As some GPCR ligands can activate and 5-HT2B — an in vitro experiment these contact points may be an unrelated receptors (for example, approaches showed that a compound identified evolutionarily conserved scaffold and serotonin (5-HT) can activate both may help in by this approach had similar inhibi- could help in future GPCR modelling GPCRs and ion channels), Shoichet characterizing tion constant values for both of these or engineering experiments. and colleagues conducted a pioneering receptors. Two other new GPCR Regarding the ligand-binding ligand-based classification of the other members pairs were similarly related by finding, pocket and changes during receptor class A (rhodopsin-like) family of of the GPCR for the first time, a ligand that bound activation, most of the ligand- GPCRs to see whether it would yield family… as well to both. contacting residues reside on the unexpected relationships in com- Notably, 485 non-GPCRs were TM3, TM6 and TM7 helices (except parison with the more traditional as in identifying found to be closely related to at least for the GPCRs CXCR4 and the sequence- and/or structure-based novel ligands one GPCR by ligand similarities. neurotensin receptor NTS1R), and classification of such receptors. such as those Three pairs of targets were also tested receptor activation leads to common They used the ChEMBL database and shown to share a ligand, including rearrangements in the TM bundle. and the chemoinformatic similarity that have the chemokine receptor CXCR2 and Furthermore, given the involvement of ensemble approach to calculate desirable casein kinase 1. So, although there almost every residue on the TM3 helix dendograms and an ‘expectation value’ activity against are important limitations to the in maintaining conserved interhelical (E-value) that scores how closely the multiple GPCRs approach, including a 50% false- contacts upon binding to a ligand or receptors relate to each other based on positive rate regarding the E-values G protein, the authors suggest that the chemical characteristics of known and the ligands not being distin- TM3 plays the part of a “structural ligands for each receptor. guished by their mode of action and functional hub” in the GPCR fold. In contrast to the sequence-based (that is, binding to orthosteric or Together, these approaches may dendogram, which clustered similar allosteric sites), it could be valuable help in characterizing other members receptors together as expected, the in identifying molecules with desir- of the GPCR family for which no ligand-based dendogram revealed able polypharmacological properties. ligand has been found (orphan new relationships. For example, the In the paper by Babu and receptors) or high-resolution structure muscarinic receptors were separated colleagues, a systematic analysis obtained, as well as in identifying novel from other biogenic amine GPCRs of the published data of solved ligands such as those that have desir- and moved towards the chemokine GPCR structures (more than 75, able activity against multiple GPCRs receptors, even though they have a all belonging to the class A family) and other unrelated protein families. lower level of similarity based on the enabled them to identify key simi- Man Tsuey Tse sequence of their orthosteric ligand- larities among the three main GPCR binding sites. domains: the extracellular, transmem- ORIGINAL RESEARCH PAPERS Lin, H. et al. A pharmacological organization of G protein- Interestingly, many of the GPCRs brane (TM) and intracellular regions. coupled receptors. Nature Methods 10, 140–146 that became neighbours according Among the detailed observations (2013) | Venkatakrishnan, A. J. et al. Molecular to their ligand-based similarities did noted by the authors, they identified a signatures of G protein-coupled receptors. Nature 494, 185–194 (2013) not share any known ligands, and network of 24 non-covalent contacts

NATURE REVIEWS | DRUG DISCOVERY VOLUME 12 | MARCH 2013