2. Academic Validation
  3. Activation and allosteric regulation of the orphan GPR88-Gi1 signaling complex

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

  • Nat Commun. 2022 May 2;13(1):2375. doi: 10.1038/s41467-022-30081-5.
Geng Chen  # 1 2,  Jun Xu  # 1 3,  Asuka Inoue  # 4,  Maximilian F Schmidt  # 5,  Chen Bai 6,  Qiuyuan Lu 1,  Peter Gmeiner 7,  Zheng Liu 8,  Yang Du 9
Affiliations

Affiliations

  • 1 Kobilka Institute of Innovative Drug Discovery, School of Medicine, Chinese University of Hong Kong, Shenzhen, Guangdong, 518172, China.
  • 2 School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, 230026, China.
  • 3 Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, 94305, USA.
  • 4 Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, 980-8578, Japan. iaska@tohoku.ac.jp.
  • 5 Department of Chemistry and Pharmacy, Medicinal Chemistry, Friedrich-Alexander University Erlangen-Nürnberg, Nikolaus-Fiebiger-Straße 10, Erlangen, 91058, Germany.
  • 6 Warshel Institute for Computational Biology, School of Medicine, Chinese University of Hong Kong, Shenzhen, Guangdong, 518172, China.
  • 7 Department of Chemistry and Pharmacy, Medicinal Chemistry, Friedrich-Alexander University Erlangen-Nürnberg, Nikolaus-Fiebiger-Straße 10, Erlangen, 91058, Germany. peter.gmeiner@fau.de.
  • 8 Kobilka Institute of Innovative Drug Discovery, School of Medicine, Chinese University of Hong Kong, Shenzhen, Guangdong, 518172, China. liuzheng@cuhk.edu.cn.
  • 9 Kobilka Institute of Innovative Drug Discovery, School of Medicine, Chinese University of Hong Kong, Shenzhen, Guangdong, 518172, China. yangdu@cuhk.edu.cn.
  • # Contributed equally.
PMID: 35501348 DOI: 10.1038/s41467-022-30081-5
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.

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