Rules and mechanisms governing G protein coupling selectivity of GPCRs

• DOI: 10.1016/j.celrep.2023.113173
• Publication Date: 2023-09-23T00:14:58Z
• Authors: Ikuo Masuho; Ryoji Kise; Pablo Gainza; Ee Von Moo; Xiaona Li; Ryosuke Tany; Hideko Wakasugi-M...; Bruno E. Correia; Kirill A. Martemy...
• Keywords: Diversity; QH301-705.5; Activation; Article; Receptors, G-Protein-Coupled; Complexes; GTP-Binding Proteins; CP: Cell biology; Biology (General); Carrier Proteins; Determinants; Algorithms; Receptor; Signal Transduction

G protein-coupled receptors (GPCRs) convert extracellular stimuli into intracellular signaling by coupling to heterotrimeric G proteins of four classes: Gi/o, Gq, Gs, and G12/13. However, our understanding of the G protein selectivity of GPCRs is incomplete. Here, we quantitatively measure the enzymatic activity of GPCRs in living cells and reveal the G protein selectivity of 124 GPCRs with the exact rank order of their G protein preference. Using this information, we establish a classification of GPCRs by functional selectivity, discover the existence of a G12/13-coupled receptor, G15-coupled receptors, and a variety of subclasses for Gi/o-, Gq-, and Gs-coupled receptors, culminating in development of the predictive algorithm of G protein selectivity. We further identify the structural determinants of G protein selectivity, allowing us to synthesize non-existent GPCRs with de novo G protein selectivity and efficiently identify putative pathogenic variants.