Laboratory of Receptor Structure and Signaling, HIT Center for Life Sciences, School of Life Science and Technology, Harbin Institute of Technology, Harbin 150001, China.
Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Aoba, Aramaki, Aoba-ku, Sendai, Miyagi 980-8578, Japan.
Cell Chem Biol. 2024 Nov 21;31(11):1899-1908.e5. doi: 10.1016/j.chembiol.2024.08.005. Epub 2024 Sep 11.
The lysophosphatidylserine (LysoPS) receptor P2Y10, also known as LPS, 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 G 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 Gα engagement of P2Y10 and identifies key determinants for Gα-vs.-Gα-coupling selectivity, whose mutations selectively disrupt Gα engagement while preserving the intact coupling of Gα. The combined structural and functional studies provide insights into the molecular mechanisms of LysoPS recognition and Gα coupling specificity.
溶血磷脂酰丝氨酸（LysoPS）受体 P2Y10，也称为 LPS，在调节免疫反应中发挥着关键作用，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 异源三聚体蛋白复合物的冷冻电镜（cryo-EM）结构。该结构和突变研究强调了一个全面的极性网络在促进 LysoPS 与受体结合和激活方面的主要作用。这种相互作用模式在 GPR174 中得到保留，但在 GPR34 中不存在。此外，我们的结构研究揭示了 P2Y10 与 Gα 结合的基本相互作用，并确定了 Gα-与 Gα 偶联选择性的关键决定因素，其突变选择性地破坏了 Gα 的结合，同时保持了完整的 Gα 偶联。综合结构和功能研究为 LysoPS 识别和 Gα 偶联特异性的分子机制提供了深入了解。
