Cryo-EM structure of human GPR158 receptor coupled to the RGS7-Gβ5 signaling complex.

Dipak N Patil,Shikha Singh,Scott J Novick,Thibaut Laboute,Timothy S Strutzenberg,Patrick R Griffin,Appu K Singh,John F Hunt,Carol V Robinson,Tina Izard,Di Wu,Xingyu Qiu,Kirill A Martemyanov

doi:10.1126/science.abl4732

Abstract

GPR158 is an orphan G protein–coupled receptor (GPCR) 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 mechanisms of GPR158 are largely unknown. We used single-particle cryo–electron microscopy (cryo-EM) to determine the structures of human GPR158 alone and bound to an RGS signaling complex. The structures reveal a homodimeric organization stabilized by a pair of phospholipids and the presence of an extracellular Cache domain, an unusual ligand-binding domain in GPCRs. We further demonstrate the structural basis of GPR158 coupling to RGS7-Gβ5. Together, these results provide insights into the unusual biology of orphan receptors and the formation of GPCR-RGS complexes.

Highlights

Orphan G-protein-coupled receptor (GPCR) are attractive drug targets with important roles in physiology and disease (9, 10)
We further detected two phospholipids in the cavity generated by the dimeric interface and several cholesterol-like molecules packed against hydrophobic residues of the TM domain, including the dimeric interface
We observed densities for two phospholipids at the cavity formed by the TM dimeric interface and performed massspectrometry to identify lipids co-purified with GPR158 complex

Summary

Introduction

Orphan GPCRs are attractive drug targets with important roles in physiology and disease (9, 10). The structure of GPR158 reveals a homodimer assembly (Fig. 1A) where the dimerization interface involves the extracellular domain, the transmembrane (TM) region, and cytoplasmic elements We observed densities for two phospholipids at the cavity formed by the TM dimeric interface and performed massspectrometry to identify lipids co-purified with GPR158 complex

Results

Conclusion