变构调节
孤儿受体
G蛋白偶联受体
药物发现
配体(生物化学)
变构调节剂
化学
细胞生物学
生物
生物化学
信号转导
受体
转录因子
基因
作者
Geng Chen,Jun Xu,Asuka Inoue,Maximilian F. Schmidt,Chen Bai,Qiuyuan Lu,Peter Gmeiner,Zheng Liu,Yang Du
标识
DOI:10.1038/s41467-022-30081-5
摘要
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.
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