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-Structure paper
タイトル | Activation and allosteric regulation of the orphan GPR88-Gi1 signaling complex. |
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ジャーナル・号・ページ | Nat Commun, Vol. 13, Issue 1, Page 2375, Year 2022 |
掲載日 | 2022年5月2日 |
著者 | Geng Chen / Jun Xu / Asuka Inoue / Maximilian F Schmidt / Chen Bai / Qiuyuan Lu / Peter Gmeiner / Zheng Liu / Yang Du / |
PubMed 要旨 | 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 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 α5 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. |
リンク | Nat Commun / PubMed:35501348 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 2.4 - 3.0 Å |
構造データ | EMDB-31164, PDB-7ejx: EMDB-32904, PDB-7wz4: |
化合物 | ChemComp-J5F: ChemComp-CLR: ChemComp-HOH: |
由来 |
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キーワード | MEMBRANE PROTEIN / GPR88 / signaling complex / cryo-EM |