IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-56131-2.html
   My bibliography  Save this article

Identification of a binding site for small molecule inhibitors targeting human TRPM4

Author

Listed:
  • Babatunde Ekundayo

    (Rt. de la Sorge)

  • Prakash Arullampalam

    (University of Bern)

  • Christian E. Gerber

    (University of Bern)

  • Anne-Flore Hämmerli

    (University of Bern)

  • Sabrina Guichard

    (University of Bern)

  • Mey Boukenna

    (University of Bern)

  • Daniela Ross-Kaschitza

    (University of Bern)

  • Martin Lochner

    (University of Bern)

  • Jean-Sebastien Rougier

    (University of Bern)

  • Henning Stahlberg

    (Rt. de la Sorge)

  • Hugues Abriel

    (University of Bern)

  • Dongchun Ni

    (Rt. de la Sorge
    Shenzhen University)

Abstract

Transient receptor potential (TRP) melastatin 4 (TRPM4) protein is a calcium-activated monovalent cation channel associated with various genetic and cardiovascular disorders. The anthranilic acid derivative NBA is a potent and specific TRPM4 inhibitor, but its binding site in TRPM4 has been unknown, although this information is crucial for drug development targeting TRPM4. We determine three cryo-EM structures of full-length human TRPM4 embedded in native lipid nanodiscs without inhibitor, bound to NBA, and an anthranilic acid derivative, IBA. We found that the small molecules NBA and IBA were bound in a pocket formed between the S3, S4, and TRP helices and the S4-S5 linker of TRPM4. Our structural data and results from patch clamp experiments enable validation of a binding site for small molecule inhibitors, paving the way for further drug development targeting TRPM4.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56131-2
    DOI: 10.1038/s41467-025-56131-2
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-56131-2
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-025-56131-2?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. Jinhong Hu & Sung Jin Park & Tyler Walter & Ian J. Orozco & Garrett O‘Dea & Xinyu Ye & Juan Du & Wei Lü, 2024. "Physiological temperature drives TRPM4 ligand recognition and gating," Nature, Nature, vol. 630(8016), pages 509-515, June.
    2. Paige A. Winkler & Yihe Huang & Weinan Sun & Juan Du & Wei Lü, 2017. "Electron cryo-microscopy structure of a human TRPM4 channel," Nature, Nature, vol. 552(7684), pages 200-204, December.
    3. Jiangtao Guo & Ji She & Weizhong Zeng & Qingfeng Chen & Xiao-chen Bai & Youxing Jiang, 2017. "Structures of the calcium-activated, non-selective cation channel TRPM4," Nature, Nature, vol. 552(7684), pages 205-209, December.
    4. David E. Clapham, 2003. "TRP channels as cellular sensors," Nature, Nature, vol. 426(6966), pages 517-524, December.
    5. 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.
    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. Jiangtao Zhang & Yiqiang Shi & Junping Fan & Huiwen Chen & Zhanyi Xia & Bo Huang & Juquan Jiang & Jianke Gong & Zhuo Huang & Daohua Jiang, 2022. "N-type fast inactivation of a eukaryotic voltage-gated sodium channel," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    2. Filomena Perri & Adriana Coricello & James D. Adams, 2020. "Monoterpenoids: The Next Frontier in the Treatment of Chronic Pain?," J, MDPI, vol. 3(2), pages 1-20, May.
    3. Catherine A. Doyle & Gregory W. Busey & Wesley H. Iobst & Volker Kiessling & Chloe Renken & Hansa Doppalapudi & Marta E. Stremska & Mohan C. Manjegowda & Mohd Arish & Weiming Wang & Shardul Naphade & , 2024. "Endosomal fusion of pH-dependent enveloped viruses requires ion channel TRPM7," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    4. Luciano Maria Catalfamo & Giulia Marrone & Michele Basilicata & Ilaria Vivarini & Vincenza Paolino & David Della-Morte & Francesco Saverio De Ponte & Francesca Di Daniele & Domenico Quattrone & Danilo, 2022. "The Utility of Capsicum annuum L. in Internal Medicine and In Dentistry: A Comprehensive Review," IJERPH, MDPI, vol. 19(18), pages 1-20, September.
    5. Elandia A Santos & Bruna SL Coelho & Ester Roffê & Helton C Santiago & Jacqueline I Alvarez-Leite & Lilian G Teixeira, 2018. "Topical Application of Capsaicin Reduces Weight Loss Allergen Aversion and Intestinal Mucosa Inflammation in A Food Allergy Experimental Model," Biomedical Journal of Scientific & Technical Research, Biomedical Research Network+, LLC, vol. 10(5), pages 8147-8151, November.
    6. Kirill D. Nadezhdin & Leonor Correia & Chamali Narangoda & Dhilon S. Patel & Arthur Neuberger & Thomas Gudermann & Maria G. Kurnikova & Vladimir Chubanov & Alexander I. Sobolevsky, 2023. "Structural mechanisms of TRPM7 activation and inhibition," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    7. 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.

    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:16:y:2025:i:1:d:10.1038_s41467-025-56131-2. 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.