Insights into lysophosphatidylserine recognition and Gα12/13-coupling specificity of P2Y10

The lysophosphatidylserine (LysoPS) receptor P2Y10, also known as LPS₂, plays crucial roles in the regulation of immune responses and holds promise for the treatment of autoimmune diseases. Here, we report the cryoelectron microscopy (cryo-EM) structure of LysoPS-bound P2Y10 in complex with an engineered G₁₃ heterotrimeric protein. The structure and a mutagenesis study highlight the predominant role of a comprehensive polar network in facilitating the binding and activation of the receptor by LysoPS. This interaction pattern is preserved in GPR174, but not in GPR34. Moreover, our structural study unveils the essential interactions that underlie the Gα₁₃ engagement of P2Y10 and identifies key determinants for Gα₁₂-vs.-Gα₁₃-coupling selectivity, whose mutations selectively disrupt Gα₁₂ engagement while preserving the intact coupling of Gα₁₃. The combined structural and functional studies provide insights into the molecular mechanisms of LysoPS recognition and Gα_12/13 coupling specificity.