Common coupling map advances GPCR-G protein selectivity

Abstract

Two-thirds of human hormones and one-third of clinical drugs act on membrane receptors that couple to G proteins to achieve appropriate functional responses. While G protein transducers from literature are annotated in the Guide to Pharmacology database, two recent large-scale datasets now expand the receptor-G protein couplome. However, these three datasets differ in scope and reported G protein couplings giving different coverage and conclusions on GPCR-G protein signaling. Here, we report a meta-analysis unifying GPCR-G protein coupling, by standardized normalization and consensus support, into a common coupling map. This unravels novel consensus couplings for receptors supported by two independent sources and insights on coupling selectivity of GPCRs and classification of co-coupling G proteins. The coupling protocol, map and selectivity resources will promote advances in receptor research and cellular signaling towards the exploitation of G protein signaling specificity in design of safer drugs.

Effector membrane translocation biosensors reveal G protein and βarrestin coupling profiles of 100 therapeutically relevant GPCRs

“…The novel EMTA biosensors were combined with previously described ebBRET-based βarrestin trafficking sensors (Namkung et al, 2016), providing an unprecedented description of GPCR signaling partner couplings. In addition to providing a resource to study GPCR functional selectivity (see companion paper (Hauser et al, 2021)), the sensors provide versatile and readily usable tools to study, on a large-scale, pharmacological processes such as constitutive activity, inverse agonism, ligand-biased signaling, and signaling cross-talk.…”

“…This comparative analysis revealed a number of couplings that were not reported in either GtP database or Inoue et al study (Inoue et al, 2019). EMTA identified 25 receptors that were not reported to couple to either G12 or G13 when using the same threshold on the three datasets (see companion paper (Hauser et al, 2021)). Similarly, 45 new receptor couplings to G15 were identified with EMTA.…”

“…Indeed, 27% of the receptors coupling to Gi/o only engaged this subtype family in comparison to 0, 2.4 and 9.1% for receptors activating G12/13, Gq/11 and Gs, respectively, thus displaying more promiscuous coupling. A detailed analysis of the selectivity profiles and comparison with existing data sets is presented in the accompanying paper (Hauser et al, 2021).…”

“…In the companion paper (Hauser et al, 2021), we compared the signaling profiles that we observed using the EMTA sensors with that of the chimeric G protein-based assay developed by Inoue et al (Inoue et al, 2019) and the IUPHAR/BPS Guide to Pharmacology database (GtP; https://www.guidetopharmacology.org/). This comparative analysis revealed a number of couplings that were not reported in either GtP database or Inoue et al study (Inoue et al, 2019).…”

The G protein database, GproteinDb

“…The theoretical G protein ‘couplome’ in human spans the potential interaction of these 16 G proteins with ∼800 receptors totaling 12 800 couplings or non-couplings. Recently, breakthroughs in biosensor development ( 3–6 ) yielded the first large-scale systematic quantifications of couplings ( 3 , 4 ) which have been unified in a recent meta-analysis ( 7 ). The structural elucidation of GPCR–G protein binding currently covers >120 complexes ( https://gproteindb.org/structure/gprot_statistics ) which make up a majority of the new and nearly all cryo-EM GPCR structures ( 8 ).…”