Activation and allosteric regulation of the orphan GPR88-Gi1 signaling complex

GPR88 is an orphan class A G-protein-coupled receptor that is highly expressed in the striatum and regulates diverse brain and behavioral functions. Here we present cryo-EM structures of the human GPR88-Gi1 signaling complex with or without a synthetic agonist (1R, 2R)-2-PCCA. We show that (1R, 2R)-2-PCCA is an allosteric modulator binding to a herein identified pocket formed by the cytoplasmic ends of transmembrane segments 5, 6, and the extreme C terminus of the alpha 5 helix of Gi1. We also identify an electron density in the extracellular orthosteric site that may represent a putative endogenous ligand of GPR88. These structures, together with mutagenesis studies and an inactive state model obtained from metadynamics simulations, reveal a unique activation mechanism for GPR88 with a set of distinctive structure features and a water-mediated polar network. Overall, our results provide a structural framework for understanding the ligand binding, activation and signaling mechanism of GPR88, and will facilitate the innovative drug discovery for neuropsychiatric disorders and for deorphanization of this receptor. GPR88 is an orphan GPCR and regulates diverse brain functions. Here, the authors report two structures of the human GPR88-Gi complex, showing an allosteric ligand directly involved in the interaction interface between the receptor and G-protein, and a density which may represent an endogenous ligand of GPR88.

Automated summary

This study reports two structures of the human GPR88-Gi complex, revealing an allosteric ligand involved in the interaction between the receptor and G-protein, and a potential endogenous ligand of GPR88.