Abstract
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.