TY - JOUR
T1 - Activation and allosteric regulation of the orphan GPR88-Gi1 signaling complex
AU - Chen, Geng
AU - Xu, Jun
AU - Inoue, Asuka
AU - Schmidt, Maximilian F.
AU - Bai, Chen
AU - Lu, Qiuyuan
AU - Gmeiner, Peter
AU - Liu, Zheng
AU - Du, Yang
N1 - Funding Information:
We would like to thank the Kobilka Cryo-Electron Microscopy Center, the Chinese University of Hong Kong, Shenzhen for our cryo-electron microscopy. Y.D. is supported by grants from Science, Technology and Innovation Commission of Shenzhen Municipality (Project code JCYJ20200109150019113 and SZBL2020090501011), and in part by the Kobilka Institute of Innovative Drug Discovery and Presidential Fellowship at the Chinese University of Hong Kong, Shenzhen. Z.L. is supported by the Kobilka Institute of Innovative Drug Discovery at the Chinese University of Hong Kong, Shenzhen. We thank Kouki Kawakami, Kayo Sato, Shigeko Nakano, and Ayumi Inoue (Tohoku University) for their assistance with plasmid preparation, maintenance of the cultured cells and the cell-based GPCR assays. We gratefully acknowledge the compute resources provided by the Erlangen Regional Computing Center (RRZE). A.I. was funded by the PRIME 19gm5910013, the LEAP JP19gm0010004, the BINDS JP20am0101095, and FOREST Program JPMJFR215T from the Japan Agency for Medical Research and Development (AMED); the Promotion of Science (JSPS) KAKENHI grants 21H04791, 21H05113, JPJSBP120213501, and JPJSBP120218801; Moonshot Research and Development Program JPMJMS2023; Daiichi Sankyo Foundation of Life Science; The Uehara Memorial Foundation; Ono Medical Research Foundation; Takeda Science Foundation. M.F.S. and P.G. were supported by the DFG grant GRK 1910.
Funding Information:
We would like to thank the Kobilka Cryo-Electron Microscopy Center, the Chinese University of Hong Kong, Shenzhen for our cryo-electron microscopy. Y.D. is supported by grants from Science, Technology and Innovation Commission of Shenzhen Municipality (Project code JCYJ20200109150019113 and SZBL2020090501011), and in part by the Kobilka Institute of Innovative Drug Discovery and Presidential Fellowship at the Chinese University of Hong Kong, Shenzhen. Z.L. is supported by the Kobilka Institute of Innovative Drug Discovery at the Chinese University of Hong Kong, Shenzhen. We thank Kouki Kawakami, Kayo Sato, Shigeko Nakano, and Ayumi Inoue (Tohoku University) for their assistance with plasmid preparation, maintenance of the cultured cells and the cell-based GPCR assays. We gratefully acknowledge the compute resources provided by the Erlangen Regional Computing Center (RRZE). A.I. was funded by the PRIME 19gm5910013, the LEAP JP19gm0010004, the BINDS JP20am0101095, and FOREST Program JPMJFR215T from the Japan Agency for Medical Research and Development (AMED); the Promotion of Science (JSPS) KAKENHI grants 21H04791, 21H05113, JPJSBP120213501, and JPJSBP120218801; Moonshot Research and Development Program JPMJMS2023; Daiichi Sankyo Foundation of Life Science; The Uehara Memorial Foundation; Ono Medical Research Foundation; Takeda Science Foundation. M.F.S. and P.G. were supported by the DFG grant GRK 1910.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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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U2 - 10.1038/s41467-022-30081-5
DO - 10.1038/s41467-022-30081-5
M3 - Article
C2 - 35501348
AN - SCOPUS:85129299796
SN - 2041-1723
VL - 13
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 2375
ER -