7ejx | pdb_00007ejx
Structure of the GPR88-Gi1 signaling complex bound to a synthetic ligand
Structural highlights
DiseaseGPR88_HUMAN The disease is caused by variants affecting the gene represented in this entry. FunctionGPR88_HUMAN Probable G-protein coupled receptor implicated in a large repertoire of behavioral responses that engage motor activities, spatial learning, and emotional processing. May play a role in the regulation of cognitive and motor function.[UniProtKB:Q9EPB7][UniProtKB:Q9ESP4] Publication Abstract from PubMedGPR88 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 alpha5 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. Activation and allosteric regulation of the orphan GPR88-Gi1 signaling complex.,Chen G, Xu J, Inoue A, Schmidt MF, Bai C, Lu Q, Gmeiner P, Liu Z, Du Y Nat Commun. 2022 May 2;13(1):2375. doi: 10.1038/s41467-022-30081-5. PMID:35501348[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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