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.

溶血磷脂酰丝氨酸 (LysoPS) 受体 P2Y10，也称为 LPS ₂ ，在免疫反应的调节中发挥着至关重要的作用，并有望用于治疗自身免疫性疾病。在这里，我们报告了 LysoPS 结合的 P2Y10 与工程化的 G ₁₃异三聚蛋白复合物的冷冻电子显微镜 (cryo-EM) 结构。该结构和诱变研究强调了综合极性网络在促进 LysoPS 受体结合和激活中的主导作用。这种相互作用模式在 GPR174 中保留，但在 GPR34 中没有。此外，我们的结构研究揭示了 P2Y10 的 Gα ₁₃接合基础上的基本相互作用，并确定了 Gα ₁₂ -与 -Gα _{13 -}偶联选择性的关键决定因素，其突变选择性破坏 Gα ₁₂接合，同时保留 Gα ₁₃的完整偶联。结构和功能相结合的研究为 LysoPS 识别和 Gα _{12/ 13}偶联特异性的分子机制提供了见解。