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

Babatunde Ekundayo, Prakash Arullampalam, Christian E. Gerber, Anne-Flore Hämmerli, Sabrina Guichard, Mey Boukenna, Daniela Ross-Kaschitza, Martin Lochner, Jean-Sebastien Rougier, Henning Stahlberg (), Hugues Abriel () and Dongchun Ni
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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

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-56131-2

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