Specific binding of GPR174 by endogenous lysophosphatidylserine leads to high constitutive G_s signaling.

ABSTRACT: Many orphan G protein-coupled receptors (GPCRs) remain understudied because their endogenous ligands are unknown. Here, we show that a group of class A/rhodopsin-like orphan GPCRs including GPR61, GPR161 and GPR174 increase the cAMP level similarly to fully activated D1 dopamine receptor (D1R). We report cryo-electron microscopy structures of the GPR61‒G_s, GPR161‒G_s and GPR174‒G_s complexes without any exogenous ligands. The GPR174 structure reveals that endogenous lysophosphatidylserine (lysoPS) is copurified. While GPR174 fails to respond to exogenous lysoPS, likely owing to its maximal activation by the endogenous ligand, GPR174 mutants with lower ligand binding affinities can be specifically activated by lysoPS but not other lipids, in a dose-dependent m

SUBMITTER: Nie Y 

PROVIDER: S-EPMC10516915 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature