Structure of the class C orphan GPCR GPR158 in complex with RGS7-G beta 5

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 G alpha i/o protein signaling through the RGS7-G beta 5 heterodimer. Here, we report the cryo-EM structures of GPR158 alone and in complex with one or two RGS7-G beta 5 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. The orphan GPR158 receptor belongs to the class C GPCR family and interacts with the regulator of G protein signaling 7 (RGS7)-G beta 5 complex. Here, the authors present the cryo-EM structure of human GPR158, which reveals that the extracellular domain contains a PAS domain, and they also determine the structures of GPR158 in complex with either one or two RGS7-G beta 5 heterodimers and discuss implications for the signaling mechanism.