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Structural basis of ligand recognition and self-activation of orphan GPR52

Author

Listed:
  • Xi Lin

    (ShanghaiTech University
    ShanghaiTech University
    Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Mingyue Li

    (ShanghaiTech University
    Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Niandong Wang

    (ShanghaiTech University
    ShanghaiTech University
    Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Yiran Wu

    (ShanghaiTech University)

  • Zhipu Luo

    (Soochow University)

  • Shimeng Guo

    (Shanghai Institute of Materia Medica, Chinese Academy of Sciences)

  • Gye-Won Han

    (University of Southern California)

  • Shaobai Li

    (Shanghai Jiao Tong University School of Medicine
    Shanghai Institute of Precision Medicine)

  • Yang Yue

    (ShanghaiTech University)

  • Xiaohu Wei

    (ShanghaiTech University
    Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Xin Xie

    (ShanghaiTech University
    Shanghai Institute of Materia Medica, Chinese Academy of Sciences)

  • Yong Chen

    (ShanghaiTech University
    Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Suwen Zhao

    (ShanghaiTech University
    ShanghaiTech University)

  • Jian Wu

    (Shanghai Jiao Tong University School of Medicine
    Shanghai Institute of Precision Medicine
    Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases)

  • Ming Lei

    (Shanghai Jiao Tong University School of Medicine
    Shanghai Institute of Precision Medicine
    Shanghai Jiao Tong University School of Medicine)

  • Fei Xu

    (ShanghaiTech University
    ShanghaiTech University
    Chinese Academy of Sciences)

Abstract

GPR52 is a class-A orphan G-protein-coupled receptor that is highly expressed in the brain and represents a promising therapeutic target for the treatment of Huntington’s disease and several psychiatric disorders1,2. Pathological malfunction of GPR52 signalling occurs primarily through the heterotrimeric Gs protein2, but it is unclear how GPR52 and Gs couple for signal transduction and whether a native ligand or other activating input is required. Here we present the high-resolution structures of human GPR52 in three states: a ligand-free state, a Gs-coupled self-activation state and a potential allosteric ligand-bound state. Together, our structures reveal that extracellular loop 2 occupies the orthosteric binding pocket and operates as a built-in agonist, conferring an intrinsically high level of basal activity to GPR523. A fully active state is achieved when Gs is coupled to GPR52 in the absence of an external agonist. The receptor also features a side pocket for ligand binding. These insights into the structure and function of GPR52 could improve our understanding of other self-activated GPCRs, enable the identification of endogenous and tool ligands, and guide drug discovery efforts that target GPR52.

Suggested Citation

  • Xi Lin & Mingyue Li & Niandong Wang & Yiran Wu & Zhipu Luo & Shimeng Guo & Gye-Won Han & Shaobai Li & Yang Yue & Xiaohu Wei & Xin Xie & Yong Chen & Suwen Zhao & Jian Wu & Ming Lei & Fei Xu, 2020. "Structural basis of ligand recognition and self-activation of orphan GPR52," Nature, Nature, vol. 579(7797), pages 152-157, March.
  • Handle: RePEc:nat:nature:v:579:y:2020:i:7797:d:10.1038_s41586-020-2019-0
    DOI: 10.1038/s41586-020-2019-0
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    Citations

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    Cited by:

    1. Yingying Nie & Zeming Qiu & Sijia Chen & Zhao Chen & Xiaocui Song & Yan Ma & Niu Huang & Jason G. Cyster & Sanduo Zheng, 2023. "Specific binding of GPR174 by endogenous lysophosphatidylserine leads to high constitutive Gs signaling," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    2. Xiaoting Li & Hao Chang & Jara Bouma & Laura V. Paus & Partha Mukhopadhyay & Janos Paloczi & Mohammed Mustafa & Cas Horst & Sanjay Sunil Kumar & Lijie Wu & Yanan Yu & Richard J. B. H. N. Berg & Antoni, 2023. "Structural basis of selective cannabinoid CB2 receptor activation," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    3. Eunyoung Jeong & Yoojoong Kim & Jihong Jeong & Yunje Cho, 2021. "Structure of the class C orphan GPCR GPR158 in complex with RGS7-Gβ5," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    4. Jiale Liang & Asuka Inoue & Tatsuya Ikuta & Ruixue Xia & Na Wang & Kouki Kawakami & Zhenmei Xu & Yu Qian & Xinyan Zhu & Anqi Zhang & Changyou Guo & Zhiwei Huang & Yuanzheng He, 2023. "Structural basis of lysophosphatidylserine receptor GPR174 ligand recognition and activation," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    5. Xi Lin & Bo Chen & Yiran Wu & Yingqi Han & Ao Qi & Junyan Wang & Zhao Yang & Xiaohu Wei & Tingting Zhao & Lijie Wu & Xin Xie & Jinpeng Sun & Jie Zheng & Suwen Zhao & Fei Xu, 2023. "Cryo-EM structures of orphan GPR21 signaling complexes," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    6. Chulwon Choi & Jungnam Bae & Seonghan Kim & Seho Lee & Hyunook Kang & Jinuk Kim & Injin Bang & Kiheon Kim & Won-Ki Huh & Chaok Seok & Hahnbeom Park & Wonpil Im & Hee-Jung Choi, 2023. "Understanding the molecular mechanisms of odorant binding and activation of the human OR52 family," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    7. Joshua A. Lees & João M. Dias & Francis Rajamohan & Jean-Philippe Fortin & Rebecca O’Connor & Jimmy X. Kong & Emily A. G. Hughes & Ethan L. Fisher & Jamison B. Tuttle & Gabrielle Lovett & Bethany L. K, 2023. "An inverse agonist of orphan receptor GPR61 acts by a G protein-competitive allosteric mechanism," Nature Communications, Nature, vol. 14(1), pages 1-12, December.

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