Visualizing an orphan receptor GPR158 and it complex with neuronal regulator RGS7-Gβ5 via cryoEM.

G protein-coupled receptors (GPCR) form the largest family of proteins (∼800 GPCRs) encoded in mammalian genomes that detect extracellular signals to program cellular response. They are essential to understanding physiology, disease, and drug development. More than 100 GPCRs are still awaits to identify its endogenous ligand and hence classified as orphan GPCRs. However, these orphan GPCRs have been implicated in several disorders from cancers to neurological diseases. Yet, in many cases, their mechanisms, ligands, and signaling reactions are poorly understood. One such orphan receptor in nervous system is GPR158 that is highly expressed in the brain where it controls synapse formation and function. GPR158 has also been implicated in depression, carcinogenesis, and cognition. However, the structural organization and signaling mechanism of GPR158 are largely unknown. We employed single-particle cryogenic electron microscopy (cryoEM) to obtain structures of GPR158 in the apo state, and in complex with RGS7-Gβ5, a regulator of GPCR signaling. The structure reveals highly unique domain organization of GPR158, not documented previously in any GPCRs structures. The homodimeric organization of protomers, phospholipids interaction and the presence of an extracellular Cache domain, an unusual ligand-binding domain in GPCRs provide insights into the unusual biology of this orphan receptor and the formation of GPCR-RGS complexes. These structures could help to deorphanize the receptor by serving the template for structure-based discovery of its ligands that would leads to exploration of mechanistic of GPR158 mediated neuronal signaling.