Masuho, IkuoKise, RyojiGainza, PabloVon Moo, EeLi, XiaonaTany, RyosukeWakasugi-Masuho, HidekoCorreia, Bruno E.Martemyanov, Kirill A.2024-02-162024-02-162024-02-162023-09-2310.1016/j.celrep.2023.113173https://infoscience.epfl.ch/handle/20.500.14299/203863WOS:001083769800001G 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.Life Sciences & BiomedicineReceptorActivationDeterminantsDiversityComplexestext::journal::journal article::research article