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Extracellular modulation of TREK-2 activity with nanobodies provides insight into the mechanisms of K2P channel regulation

Author

Listed:
  • Karin E. J. Rödström

    (University of Oxford
    University of Oxford
    University of Oxford
    University of Oxford)

  • Alexander Cloake

    (University of Oxford)

  • Janina Sörmann

    (University of Oxford
    University of Oxford)

  • Agnese Baronina

    (University of Oxford)

  • Kathryn H. M. Smith

    (University of Oxford
    University of Oxford
    University of Oxford)

  • Ashley C. W. Pike

    (University of Oxford)

  • Jackie Ang

    (University of Oxford)

  • Peter Proks

    (University of Oxford
    University of Oxford)

  • Marcus Schewe

    (Kiel University)

  • Ingelise Holland-Kaye

    (University of Oxford)

  • Simon R. Bushell

    (University of Oxford)

  • Jenna Elliott

    (University of Oxford)

  • Els Pardon

    (Vrije Universiteit Brussel
    VIB)

  • Thomas Baukrowitz

    (Kiel University)

  • Raymond J. Owens

    (The Rosalind Franklin Institute
    University of Oxford)

  • Simon Newstead

    (University of Oxford
    University of Oxford
    University of Oxford)

  • Jan Steyaert

    (Vrije Universiteit Brussel
    VIB)

  • Elisabeth P. Carpenter

    (University of Oxford
    University of Oxford)

  • Stephen J. Tucker

    (University of Oxford
    University of Oxford
    University of Oxford)

Abstract

Potassium channels of the Two-Pore Domain (K2P) subfamily, KCNK1-KCNK18, play crucial roles in controlling the electrical activity of many different cell types and represent attractive therapeutic targets. However, the identification of highly selective small molecule drugs against these channels has been challenging due to the high degree of structural and functional conservation that exists not only between K2P channels, but across the whole K+ channel superfamily. To address the issue of selectivity, here we generate camelid antibody fragments (nanobodies) against the TREK-2 (KCNK10) K2P K+ channel and identify selective binders including several that directly modulate channel activity. X-ray crystallography and CryoEM data of these nanobodies in complex with TREK-2 also reveal insights into their mechanisms of activation and inhibition via binding to the extracellular loops and Cap domain, as well as their suitability for immunodetection. These structures facilitate design of a biparatropic inhibitory nanobody with markedly improved sensitivity. Together, these results provide important insights into TREK channel gating and provide an alternative, more selective approach to modulation of K2P channel activity via their extracellular domains.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48536-2
    DOI: 10.1038/s41467-024-48536-2
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    References listed on IDEAS

    as
    1. Prafulla Aryal & Firdaus Abd-Wahab & Giovanna Bucci & Mark S. P. Sansom & Stephen J. Tucker, 2014. "A hydrophobic barrier deep within the inner pore of the TWIK-1 K2P potassium channel," Nature Communications, Nature, vol. 5(1), pages 1-9, September.
    2. 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.
    3. Stephen G. Brohawn & Ernest B. Campbell & Roderick MacKinnon, 2014. "Physical mechanism for gating and mechanosensitivity of the human TRAAK K+ channel," Nature, Nature, vol. 516(7529), pages 126-130, December.
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