Common coupling map advances GPCR-G protein selectivity

Common coupling map advances GPCR-G protein selectivity

Elife. 2022 Mar 18;11:e74107. doi: 10.7554/eLife.74107.

Alexander S Hauser 1, Charlotte Avet 2, Claire Normand 3, Arturo Mancini 3, Asuka Inoue 4, Michel Bouvier 2, David E Gloriam 1

1. Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
2. Institute for Research in Immunology and Cancer (IRIC), and Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, Canada.
3. Domain Therapeutics North America, Montréal, Canada.
4. Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.


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 G protein-coupled receptor (GPCR)-G protein signaling. Here, we report a common coupling map uncovering novel couplings supported by both large-scale studies, the selectivity/promiscuity of GPCRs and G proteins, and how the co-coupling and co-expression of G proteins compare to the families from phylogenetic relationships. The coupling map and insights on GPCR-G protein selectivity will catalyze advances in receptor research and cellular signaling toward the exploitation of G protein signaling bias in design of safer drugs.

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