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

Geng Chen, Jun Xu, Asuka Inoue (), Maximilian F. Schmidt, Chen Bai, Qiuyuan Lu, Peter Gmeiner (), Zheng Liu () and Yang Du ()
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Geng Chen: Chinese University of Hong Kong
Jun Xu: Chinese University of Hong Kong
Asuka Inoue: Tohoku University
Maximilian F. Schmidt: Friedrich-Alexander University Erlangen-Nürnberg, Nikolaus-Fiebiger-Straße 10
Chen Bai: Chinese University of Hong Kong
Qiuyuan Lu: Chinese University of Hong Kong
Peter Gmeiner: Friedrich-Alexander University Erlangen-Nürnberg, Nikolaus-Fiebiger-Straße 10
Zheng Liu: Chinese University of Hong Kong
Yang Du: Chinese University of Hong Kong

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-30081-5

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