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

Structural approach to identify endogenous ligands of oGPCRs

In addition to increasing cAMP levels, caoGPCRs recruit Gα_s more efficiently than most other oGPCRs (Fig. 1a and Supplementary Table 1), as shown by NanoBiT mini-Gα_s recruitment assay²⁴. Moreover, they all contain a large hydrophobic residue (L, M, or F) at position 34.51 of the second intracellular loop (ICL2) (Fig. 1b), which is essential for G_s coupling²⁵. These results indicate that caoGPCRs can increase the cAMP level through G_s. Notably, the cAMP levels induced by expression of GPR174 alone are almost two-fold of those…