Rules and mechanisms governing G protein coupling selectivity of GPCRs

Cell Rep. 2023 Oct 31;42(10):113173. doi: 10.1016/j.celrep.2023.113173. Epub 2023 Sep 23.

Abstract

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.

Keywords: BRET assay; CP: Cell biology; G protein; GEF activity; GPCR; Gα; classification; genetic variation; signaling bias; systems biology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Carrier Proteins / metabolism
  • GTP-Binding Proteins* / metabolism
  • Receptors, G-Protein-Coupled* / metabolism
  • Signal Transduction / physiology

Substances

  • Receptors, G-Protein-Coupled
  • GTP-Binding Proteins
  • Carrier Proteins