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Structures of a mammalian TRPM8 in closed state

Author

Listed:
  • Cheng Zhao

    (Zhejiang University School of Medicine)

  • Yuan Xie

    (Fourth Military Medical University)

  • Lizhen Xu

    (Zhejiang University School of Medicine)

  • Fan Ye

    (Zhejiang University School of Medicine)

  • Ximing Xu

    (Ocean University of China)

  • Wei Yang

    (Zhejiang University School of Medicine
    Zhejiang University)

  • Fan Yang

    (Zhejiang University School of Medicine
    Zhejiang University
    Alibaba-Zhejiang University Joint Research Center of Future Digital Healthcare
    Zhejiang University Medical Center)

  • Jiangtao Guo

    (Zhejiang University School of Medicine
    Zhejiang University
    Zhejiang University Medical Center
    Zhejiang University)

Abstract

Transient receptor potential melastatin 8 (TRPM8) channel is a Ca2+-permeable non-selective cation channel that acts as the primary cold sensor in humans. TRPM8 is also activated by ligands such as menthol, icilin, and phosphatidylinositol 4,5-bisphosphate (PIP2), and desensitized by Ca2+. Here we have determined electron cryo-microscopy structures of mouse TRPM8 in the absence of ligand, and in the presence of Ca2+ and icilin at 2.5–3.2 Å resolution. The ligand-free state TRPM8 structure represents the full-length structure of mammalian TRPM8 channels with a canonical S4-S5 linker and the clearly resolved selectivity filter and outer pore loop. TRPM8 has a short but wide selectivity filter which may account for its permeability to hydrated Ca2+. Ca2+ and icilin bind in the cytosolic-facing cavity of the voltage-sensing-like domain of TRPM8 but induce little conformational change. All the ligand-bound TRPM8 structures adopt the same closed conformation as the ligand-free structure. This study reveals the overall architecture of mouse TRPM8 and the structural basis for its ligand recognition.

Suggested Citation

  • Cheng Zhao & Yuan Xie & Lizhen Xu & Fan Ye & Ximing Xu & Wei Yang & Fan Yang & Jiangtao Guo, 2022. "Structures of a mammalian TRPM8 in closed state," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30919-y
    DOI: 10.1038/s41467-022-30919-y
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    References listed on IDEAS

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    Cited by:

    1. Amy Clarke & Julia Skerjanz & Mathias A. F. Gsell & Patrick Wiedner & Hazel Erkan-Candag & Klaus Groschner & Thomas Stockner & Oleksandra Tiapko, 2024. "PIP2 modulates TRPC3 activity via TRP helix and S4-S5 linker," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    2. Babatunde Ekundayo & Prakash Arullampalam & Christian E. Gerber & Anne-Flore Hämmerli & Sabrina Guichard & Mey Boukenna & Daniela Ross-Kaschitza & Martin Lochner & Jean-Sebastien Rougier & Henning Sta, 2025. "Identification of a binding site for small molecule inhibitors targeting human TRPM4," Nature Communications, Nature, vol. 16(1), pages 1-14, December.

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