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Structure, function and pharmacology of human itch GPCRs

Author

Listed:
  • Can Cao

    (University of North Carolina at Chapel Hill School of Medicine)

  • Hye Jin Kang

    (University of North Carolina at Chapel Hill School of Medicine)

  • Isha Singh

    (University of California San Francisco, School of Medicine)

  • He Chen

    (Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai)

  • Chengwei Zhang

    (Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai)

  • Wenlei Ye

    (University of California, San Francisco)

  • Byron W. Hayes

    (Duke University Medical Center)

  • Jing Liu

    (Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai)

  • Ryan H. Gumpper

    (University of North Carolina at Chapel Hill School of Medicine)

  • Brian J. Bender

    (University of California San Francisco, School of Medicine)

  • Samuel T. Slocum

    (University of North Carolina at Chapel Hill School of Medicine)

  • Brian E. Krumm

    (University of North Carolina at Chapel Hill School of Medicine)

  • Katherine Lansu

    (University of North Carolina at Chapel Hill School of Medicine)

  • John D. McCorvy

    (University of North Carolina at Chapel Hill School of Medicine
    Medical College of Wisconsin)

  • Wesley K. Kroeze

    (University of North Carolina at Chapel Hill School of Medicine)

  • Justin G. English

    (University of North Carolina at Chapel Hill School of Medicine
    University of Utah School of Medicine)

  • Jeffrey F. DiBerto

    (University of North Carolina at Chapel Hill School of Medicine)

  • Reid H. J. Olsen

    (University of North Carolina at Chapel Hill School of Medicine)

  • Xi-Ping Huang

    (University of North Carolina at Chapel Hill School of Medicine)

  • Shicheng Zhang

    (University of North Carolina at Chapel Hill School of Medicine)

  • Yongfeng Liu

    (University of North Carolina at Chapel Hill School of Medicine)

  • Kuglae Kim

    (University of North Carolina at Chapel Hill School of Medicine)

  • Joel Karpiak

    (University of California San Francisco, School of Medicine)

  • Lily Y. Jan

    (University of California, San Francisco
    Howard Hughes Medical Institute)

  • Soman N. Abraham

    (Duke University Medical Center
    Duke–National University of Singapore)

  • Jian Jin

    (Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai)

  • Brian K. Shoichet

    (University of California San Francisco, School of Medicine)

  • Jonathan F. Fay

    (University of North Carolina at Chapel Hill School of Medicine)

  • Bryan L. Roth

    (University of North Carolina at Chapel Hill School of Medicine)

Abstract

The MRGPRX family of receptors (MRGPRX1–4) is a family of mas-related G-protein-coupled receptors that have evolved relatively recently1. Of these, MRGPRX2 and MRGPRX4 are key physiological and pathological mediators of itch and related mast cell-mediated hypersensitivity reactions2–5. MRGPRX2 couples to both Gi and Gq in mast cells6. Here we describe agonist-stabilized structures of MRGPRX2 coupled to Gi1 and Gq in ternary complexes with the endogenous peptide cortistatin-14 and with a synthetic agonist probe, respectively, and the development of potent antagonist probes for MRGPRX2. We also describe a specific MRGPRX4 agonist and the structure of this agonist in a complex with MRGPRX4 and Gq. Together, these findings should accelerate the structure-guided discovery of therapeutic agents for pain, itch and mast cell-mediated hypersensitivity.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:nature:v:600:y:2021:i:7887:d:10.1038_s41586-021-04126-6
    DOI: 10.1038/s41586-021-04126-6
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    Cited by:

    1. Edin Muratspahić & Kristine Deibler & Jianming Han & Nataša Tomašević & Kirtikumar B. Jadhav & Aina-Leonor Olivé-Marti & Nadine Hochrainer & Roland Hellinger & Johannes Koehbach & Jonathan F. Fay & Mo, 2023. "Design and structural validation of peptide–drug conjugate ligands of the kappa-opioid receptor," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    2. 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.
    3. 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.
    4. Yang Yang & Hye Jin Kang & Ruogu Gao & Jingjing Wang & Gye Won Han & Jeffrey F. DiBerto & Lijie Wu & Jiahui Tong & Lu Qu & Yiran Wu & Ryan Pileski & Xuemei Li & Xuejun Cai Zhang & Suwen Zhao & Terry K, 2023. "Structural insights into the human niacin receptor HCA2-Gi signalling complex," Nature Communications, Nature, vol. 14(1), pages 1-11, December.

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