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Structure, function and pharmacology of human itch receptor complexes

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Listed:
  • Fan Yang

    (Peking University, Ministry of Education
    Peking University
    Shandong University School of Medicine
    Shandong University School of Medicine)

  • Lulu Guo

    (Shandong University School of Medicine)

  • Yu Li

    (Peking University, Ministry of Education
    Peking University)

  • Guopeng Wang

    (Peking University
    Peking University)

  • Jia Wang

    (Shandong University School of Medicine)

  • Chao Zhang

    (Shandong University School of Medicine)

  • Guo-Xing Fang

    (Shandong University School of Medicine
    Guangzhou University of Chinese Medicine)

  • Xu Chen

    (Shandong University School of Medicine)

  • Lei Liu

    (Shandong University School of Medicine)

  • Xu Yan

    (Shandong University School of Medicine)

  • Qun Liu

    (Shandong University School of Medicine)

  • Changxiu Qu

    (Peking University, Ministry of Education
    Shandong University School of Medicine)

  • Yunfei Xu

    (Qilu Hospital of Shandong University)

  • Peng Xiao

    (Shandong University School of Medicine)

  • Zhongliang Zhu

    (University of Science and Technology of China)

  • Zijian Li

    (Peking University Third Hospital, Research)

  • Jiuyao Zhou

    (Guangzhou University of Chinese Medicine)

  • Xiao Yu

    (Shandong University School of Medicine)

  • Ning Gao

    (Peking University)

  • Jin-Peng Sun

    (Peking University, Ministry of Education
    Shandong University School of Medicine
    Shandong University)

Abstract

In the clades of animals that diverged from the bony fish, a group of Mas-related G-protein-coupled receptors (MRGPRs) evolved that have an active role in itch and allergic signals1,2. As an MRGPR, MRGPRX2 is known to sense basic secretagogues (agents that promote secretion) and is involved in itch signals and eliciting pseudoallergic reactions3–6. MRGPRX2 has been targeted by drug development efforts to prevent the side effects induced by certain drugs or to treat allergic diseases. Here we report a set of cryo-electron microscopy structures of the MRGPRX2–Gi1 trimer in complex with polycationic compound 48/80 or with inflammatory peptides. The structures of the MRGPRX2–Gi1 complex exhibited shallow, solvent-exposed ligand-binding pockets. We identified key common structural features of MRGPRX2 and describe a consensus motif for peptidic allergens. Beneath the ligand-binding pocket, the unusual kink formation at transmembrane domain 6 (TM6) and the replacement of the general toggle switch from Trp6.48 to Gly6.48 (superscript annotations as per Ballesteros–Weinstein nomenclature) suggest a distinct activation process. We characterized the interfaces of MRGPRX2 and the Gi trimer, and mapped the residues associated with key single-nucleotide polymorphisms on both the ligand and G-protein interfaces of MRGPRX2. Collectively, our results provide a structural basis for the sensing of cationic allergens by MRGPRX2, potentially facilitating the rational design of therapies to prevent unwanted pseudoallergic reactions.

Suggested Citation

  • Fan Yang & Lulu Guo & Yu Li & Guopeng Wang & Jia Wang & Chao Zhang & Guo-Xing Fang & Xu Chen & Lei Liu & Xu Yan & Qun Liu & Changxiu Qu & Yunfei Xu & Peng Xiao & Zhongliang Zhu & Zijian Li & Jiuyao Zh, 2021. "Structure, function and pharmacology of human itch receptor complexes," Nature, Nature, vol. 600(7887), pages 164-169, December.
  • Handle: RePEc:nat:nature:v:600:y:2021:i:7887:d:10.1038_s41586-021-04077-y
    DOI: 10.1038/s41586-021-04077-y
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    Cited by:

    1. Li-Hua Zhao & Jingyu Lin & Su-Yu Ji & X. Edward Zhou & Chunyou Mao & Dan-Dan Shen & Xinheng He & Peng Xiao & Jinpeng Sun & Karsten Melcher & Yan Zhang & Xiao Yu & H. Eric Xu, 2022. "Structure insights into selective coupling of G protein subtypes by a class B G protein-coupled receptor," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    2. Xuan Zhang & Guibing Liu & Ya-Ni Zhong & Ru Zhang & Chuan-Cheng Yang & Canyang Niu & Xuanyu Pu & Jingjing Sun & Tianyao Zhang & Lejin Yang & Chao Zhang & Xiu Li & Xinyuan Shen & Peng Xiao & Jin-Peng S, 2024. "Structural basis of ligand recognition and activation of the histamine receptor family," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    3. Lulu Guo & Yumu Zhang & Guoxing Fang & Lu Tie & Yuming Zhuang & Chenyang Xue & Qi Liu & Minghui Zhang & Kongkai Zhu & Chongzhao You & Peiyu Xu & Qingning Yuan & Chao Zhang & Lei Liu & Naikang Rong & S, 2023. "Ligand recognition and G protein coupling of the human itch receptor MRGPRX1," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    4. Yunxuan Lei & Xin Guo & Yanping Luo & Xiaoyin Niu & Yebin Xi & Lianbo Xiao & Dongyi He & Yanqin Bian & Yong Zhang & Li Wang & Xiaochun Peng & Zhaojun Wang & Guangjie Chen, 2024. "Synovial microenvironment-influenced mast cells promote the progression of rheumatoid arthritis," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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