IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v12y2021i1d10.1038_s41467-021-27435-w.html
   My bibliography  Save this article

Small molecule modulation of the Drosophila Slo channel elucidated by cryo-EM

Author

Listed:
  • Tobias Raisch

    (Max Planck Institute of Molecular Physiology)

  • Andreas Brockmann

    (Bayer AG, Crop Science Division
    Rheinische Friedrich-Wilhelms-Universität Bonn)

  • Ulrich Ebbinghaus-Kintscher

    (Bayer AG, Crop Science Division)

  • Jörg Freigang

    (Bayer AG, Crop Science Division)

  • Oliver Gutbrod

    (Bayer AG, Crop Science Division)

  • Jan Kubicek

    (Cube Biotech GmbH)

  • Barbara Maertens

    (Cube Biotech GmbH)

  • Oliver Hofnagel

    (Max Planck Institute of Molecular Physiology)

  • Stefan Raunser

    (Max Planck Institute of Molecular Physiology)

Abstract

Slowpoke (Slo) potassium channels display extraordinarily high conductance, are synergistically activated by a positive transmembrane potential and high intracellular Ca2+ concentrations and are important targets for insecticides and antiparasitic drugs. However, it is unknown how these compounds modulate ion translocation and whether there are insect-specific binding pockets. Here, we report structures of Drosophila Slo in the Ca2+-bound and Ca2+-free form and in complex with the fungal neurotoxin verruculogen and the anthelmintic drug emodepside. Whereas the architecture and gating mechanism of Slo channels are conserved, potential insect-specific binding pockets exist. Verruculogen inhibits K+ transport by blocking the Ca2+-induced activation signal and precludes K+ from entering the selectivity filter. Emodepside decreases the conductance by suboptimal K+ coordination and uncouples ion gating from Ca2+ and voltage sensing. Our results expand the mechanistic understanding of Slo regulation and lay the foundation for the rational design of regulators of Slo and other voltage-gated ion channels.

Suggested Citation

  • Tobias Raisch & Andreas Brockmann & Ulrich Ebbinghaus-Kintscher & Jörg Freigang & Oliver Gutbrod & Jan Kubicek & Barbara Maertens & Oliver Hofnagel & Stefan Raunser, 2021. "Small molecule modulation of the Drosophila Slo channel elucidated by cryo-EM," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27435-w
    DOI: 10.1038/s41467-021-27435-w
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-021-27435-w
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-021-27435-w?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Youxing Jiang & Alice Lee & Jiayun Chen & Martine Cadene & Brian T. Chait & Roderick MacKinnon, 2002. "Crystal structure and mechanism of a calcium-gated potassium channel," Nature, Nature, vol. 417(6888), pages 515-522, May.
    2. Richard K. Hite & Xiao Tao & Roderick MacKinnon, 2017. "Structural basis for gating the high-conductance Ca2+-activated K+ channel," Nature, Nature, vol. 541(7635), pages 52-57, January.
    3. Xiao Tao & Richard K. Hite & Roderick MacKinnon, 2017. "Cryo-EM structure of the open high-conductance Ca2+-activated K+ channel," Nature, Nature, vol. 541(7635), pages 46-51, January.
    4. Kenton J. Swartz, 2008. "Sensing voltage across lipid membranes," Nature, Nature, vol. 456(7224), pages 891-897, December.
    5. Youxing Jiang & Alice Lee & Jiayun Chen & Martine Cadene & Brian T. Chait & Roderick MacKinnon, 2002. "The open pore conformation of potassium channels," Nature, Nature, vol. 417(6888), pages 523-526, May.
    6. Yunkun Wu & Yi Yang & Sheng Ye & Youxing Jiang, 2010. "Structure of the gating ring from the human large-conductance Ca2+-gated K+ channel," Nature, Nature, vol. 466(7304), pages 393-397, July.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Guohui Zhang & Xianjin Xu & Zhiguang Jia & Yanyan Geng & Hongwu Liang & Jingyi Shi & Martina Marras & Carlota Abella & Karl L. Magleby & Jonathan R. Silva & Jianhan Chen & Xiaoqin Zou & Jianmin Cui, 2022. "An allosteric modulator activates BK channels by perturbing coupling between Ca2+ binding and pore opening," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    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. Eva Chovancova & Antonin Pavelka & Petr Benes & Ondrej Strnad & Jan Brezovsky & Barbora Kozlikova & Artur Gora & Vilem Sustr & Martin Klvana & Petr Medek & Lada Biedermannova & Jiri Sochor & Jiri Damb, 2012. "CAVER 3.0: A Tool for the Analysis of Transport Pathways in Dynamic Protein Structures," PLOS Computational Biology, Public Library of Science, vol. 8(10), pages 1-12, October.
    4. Ruo-Xu Gu & Bert L. Groot, 2023. "Central cavity dehydration as a gating mechanism of potassium channels," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    5. Yangyang Wang & Shaokang Yang & Jingwei Zhang & Zhuo Chen & Bo Zhu & Jian Li & Shijing Liang & Yunxiang Bai & Jianhong Xu & Dewei Rao & Liangliang Dong & Chunfang Zhang & Xiaowei Yang, 2023. "Scalable and switchable CO2-responsive membranes with high wettability for separation of various oil/water systems," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    6. Turkan Haliloglu & Nir Ben-Tal, 2008. "Cooperative Transition between Open and Closed Conformations in Potassium Channels," PLOS Computational Biology, Public Library of Science, vol. 4(8), pages 1-11, August.
    7. Navid Paknejad & Vinay Sapuru & Richard K. Hite, 2023. "Structural titration reveals Ca2+-dependent conformational landscape of the IP3 receptor," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    8. Ausloos, Marcel & Ivanova, Kristinka & Siwy, Zuzanna, 2004. "Searching for self-similarity in switching time and turbulent cascades in ion transport through a biochannel. A time delay asymmetry," Physica A: Statistical Mechanics and its Applications, Elsevier, vol. 336(3), pages 319-333.
    9. Elvira Pantuso & Ejaz Ahmed & Enrica Fontananova & Adele Brunetti & Ibrahim Tahir & Durga Prasad Karothu & Nisreen Amer Alnaji & Ghada Dushaq & Mahmoud Rasras & Panče Naumov & Gianluca Profio, 2023. "Smart dynamic hybrid membranes with self-cleaning capability," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    10. Carlos A. Z. Bassetto & Flavio Costa & Carlo Guardiani & Francisco Bezanilla & Alberto Giacomello, 2023. "Noncanonical electromechanical coupling paths in cardiac hERG potassium channel," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    11. Andy K. M. Lam & Sonja Rutz & Raimund Dutzler, 2022. "Inhibition mechanism of the chloride channel TMEM16A by the pore blocker 1PBC," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    12. 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.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27435-w. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.