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Structures of the T cell potassium channel Kv1.3 with immunoglobulin modulators

Author

Listed:
  • Purushotham Selvakumar

    (Weill Cornell Medical College)

  • Ana I. Fernández-Mariño

    (National Institutes of Health)

  • Nandish Khanra

    (Weill Cornell Medical College)

  • Changhao He

    (Weill Cornell Medical College)

  • Alice J. Paquette

    (New York University School of Medicine)

  • Bing Wang

    (New York University School of Medicine)

  • Ruiqi Huang

    (Applied Biomedical Science Institute
    Minotaur Therapeutics)

  • Vaughn V. Smider

    (Applied Biomedical Science Institute
    Minotaur Therapeutics
    The Scripps Research Institute)

  • William J. Rice

    (New York University School of Medicine
    New York University School of Medicine)

  • Kenton J. Swartz

    (National Institutes of Health)

  • Joel R. Meyerson

    (Weill Cornell Medical College)

Abstract

The Kv1.3 potassium channel is expressed abundantly on activated T cells and mediates the cellular immune response. This role has made the channel a target for therapeutic immunomodulation to block its activity and suppress T cell activation. Here, we report structures of human Kv1.3 alone, with a nanobody inhibitor, and with an antibody-toxin fusion blocker. Rather than block the channel directly, four copies of the nanobody bind the tetramer’s voltage sensing domains and the pore domain to induce an inactive pore conformation. In contrast, the antibody-toxin fusion docks its toxin domain at the extracellular mouth of the channel to insert a critical lysine into the pore. The lysine stabilizes an active conformation of the pore yet blocks ion permeation. This study visualizes Kv1.3 pore dynamics, defines two distinct mechanisms to suppress Kv1.3 channel activity with exogenous inhibitors, and provides a framework to aid development of emerging T cell immunotherapies.

Suggested Citation

  • Purushotham Selvakumar & Ana I. Fernández-Mariño & Nandish Khanra & Changhao He & Alice J. Paquette & Bing Wang & Ruiqi Huang & Vaughn V. Smider & William J. Rice & Kenton J. Swartz & Joel R. Meyerson, 2022. "Structures of the T cell potassium channel Kv1.3 with immunoglobulin modulators," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31285-5
    DOI: 10.1038/s41467-022-31285-5
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    Cited by:

    1. Qiansheng Liang & Gamma Chi & Leonardo Cirqueira & Lianteng Zhi & Agostino Marasco & Nadia Pilati & Martin J. Gunthorpe & Giuseppe Alvaro & Charles H. Large & David B. Sauer & Werner Treptow & Manuel , 2024. "The binding and mechanism of a positive allosteric modulator of Kv3 channels," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    2. Karin E. J. Rödström & Alexander Cloake & Janina Sörmann & Agnese Baronina & Kathryn H. M. Smith & Ashley C. W. Pike & Jackie Ang & Peter Proks & Marcus Schewe & Ingelise Holland-Kaye & Simon R. Bushe, 2024. "Extracellular modulation of TREK-2 activity with nanobodies provides insight into the mechanisms of K2P channel regulation," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    3. Marcos Matamoros & Xue Wen Ng & Joshua B. Brettmann & David W. Piston & Colin G. Nichols, 2023. "Conformational plasticity of NaK2K and TREK2 potassium channel selectivity filters," Nature Communications, Nature, vol. 14(1), pages 1-12, December.

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