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Ligand recognition and G protein coupling of the human itch receptor MRGPRX1

Author

Listed:
  • Lulu Guo

    (Shandong University
    Shandong University School of Medicine)

  • Yumu Zhang

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

  • Guoxing Fang

    (Shandong University)

  • Lu Tie

    (Peking University)

  • Yuming Zhuang

    (Shandong University)

  • Chenyang Xue

    (Southern University of Science and Technology)

  • Qi Liu

    (Shandong University)

  • Minghui Zhang

    (Shandong University School of Medicine)

  • Kongkai Zhu

    (Shandong University School of Medicine)

  • Chongzhao You

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

  • Peiyu Xu

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

  • Qingning Yuan

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

  • Chao Zhang

    (Shandong University School of Medicine)

  • Lei Liu

    (Shandong University)

  • Naikang Rong

    (Shandong University School of Medicine)

  • Shengxuan Peng

    (Shandong University)

  • Yuan Liu

    (Shandong University)

  • Chuanzheng Wang

    (Shandong University)

  • Xin Luo

    (Shandong University)

  • Zongyao Lv

    (Shandong University)

  • Dongwei Kang

    (Shandong University)

  • Xiao Yu

    (Shandong University)

  • Cheng Zhang

    (Shandong University)

  • Yi Jiang

    (Lingang Laboratory)

  • Xinzhong Dong

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • Jiuyao Zhou

    (Guangzhou University of Chinese Medicine)

  • Zhongmin Liu

    (Southern University of Science and Technology)

  • Fan Yang

    (Shandong University
    Shandong University)

  • H. Eric Xu

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

  • Jin-Peng Sun

    (Shandong University
    Shandong University School of Medicine
    Peking University)

Abstract

MRGPRX1, a Mas-related GPCR (MRGPR), is a key receptor for itch perception and targeting MRGPRX1 may have potential to treat both chronic itch and pain. Here we report cryo-EM structures of the MRGPRX1-Gi1 and MRGPRX1-Gq trimers in complex with two peptide ligands, BAM8-22 and CNF-Tx2. These structures reveal a shallow orthosteric pocket and its conformational plasticity for sensing multiple different peptidic itch allergens. Distinct from MRGPRX2, MRGPRX1 contains a unique pocket feature at the extracellular ends of TM3 and TM4 to accommodate the peptide C-terminal “RF/RY” motif, which could serve as key mechanisms for peptidic allergen recognition. Below the ligand binding pocket, the G6.48XP6.50F6.51G6.52X(2)F/W6.55 motif is essential for the inward tilting of the upper end of TM6 to induce receptor activation. Moreover, structural features inside the ligand pocket and on the cytoplasmic side of MRGPRX1 are identified as key elements for both Gi and Gq signaling. Collectively, our studies provide structural insights into understanding itch sensation, MRGPRX1 activation, and downstream G protein signaling.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40705-z
    DOI: 10.1038/s41467-023-40705-z
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    References listed on IDEAS

    as
    1. 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.
    2. Can Cao & Hye Jin Kang & Isha Singh & He Chen & Chengwei Zhang & Wenlei Ye & Byron W. Hayes & Jing Liu & Ryan H. Gumpper & Brian J. Bender & Samuel T. Slocum & Brian E. Krumm & Katherine Lansu & John , 2021. "Structure, function and pharmacology of human itch GPCRs," Nature, Nature, vol. 600(7887), pages 170-175, December.
    Full references (including those not matched with items on IDEAS)

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