Department of Life Science, Pohang University of Science and Technology, Pohang, Republic of Korea.
Nat Commun. 2021 Nov 23;12(1):6805. doi: 10.1038/s41467-021-27147-1.
GPR158, a class C orphan GPCR, functions in cognition, stress-induced mood control, and synaptic development. Among class C GPCRs, GPR158 is unique as it lacks a Venus flytrap-fold ligand-binding domain and terminates Gαi/o protein signaling through the RGS7-Gβ5 heterodimer. Here, we report the cryo-EM structures of GPR158 alone and in complex with one or two RGS7-Gβ5 heterodimers. GPR158 dimerizes through Per-Arnt-Sim-fold extracellular and transmembrane (TM) domains connected by an epidermal growth factor-like linker. The TM domain (TMD) reflects both inactive and active states of other class C GPCRs: a compact intracellular TMD, conformations of the two intracellular loops (ICLs) and the TMD interface formed by TM4/5. The ICL2, ICL3, TM3, and first helix of the cytoplasmic coiled-coil provide a platform for the DHEX domain of one RGS7 and the second helix recruits another RGS7. The unique features of the RGS7-binding site underlie the selectivity of GPR158 for RGS7.
GPR158 是一种 C 类孤儿 GPCR，在认知、应激诱导的情绪控制和突触发育中发挥作用。在 C 类 GPCR 中，GPR158 是独一无二的，因为它缺乏 Venus flytrap 折叠配体结合域，并通过 RGS7-Gβ5 异源二聚体终止 Gαi/o 蛋白信号。在这里，我们报告了 GPR158 单独和与一个或两个 RGS7-Gβ5 异源二聚体复合物的冷冻电镜结构。GPR158 通过连接表皮生长因子样接头的 Per-Arnt-Sim 折叠细胞外和跨膜 (TM) 结构域二聚化。TM 结构域 (TMD) 反映了其他 C 类 GPCR 的非活性和活性状态：紧凑的细胞内 TMD、两个细胞内环 (ICL) 的构象以及由 TM4/5 形成的 TMD 界面。ICL2、ICL3、TM3 和细胞质卷曲螺旋的第一个螺旋为一个 RGS7 的 DHEX 结构域提供了一个平台，并招募另一个 RGS7 的第二个螺旋。RGS7 结合位点的独特特征是 GPR158 对 RGS7 的选择性的基础。
