Identification of a Binding Site for Small Molecule Inhibitors Targeting Human TRPM4

Ekundayo, B.; Arullampalam, P.; Gerber, C.; Haemmerli, A.-F.; Guichard, S.; Boukenna, M.; Ross-Kaschitza, D.; Lochner, M.; Rougier, J.-S.; Stahlberg, H.; Abriel, H.; Ni, D.

doi:10.1101/2024.01.22.576650

bioRxiv · 10.1101/2024.01.22.576650

Identification of a Binding Site for Small Molecule Inhibitors Targeting Human TRPM4

Ekundayo, B.·Arullampalam, P.·Gerber, C.·Haemmerli, A.-F.·Guichard, S.·Boukenna, M.·Ross-Kaschitza, D.·Lochner, M.·Rougier, J.-S.·Stahlberg, H.·Abriel, H.·Ni, D.

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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 determined three cryo-EM structures of full-length human TRPM4 embedded in native lipid nanodiscs without inhibitor, bound to NBA, and a new 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.

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Ekundayo, B., Arullampalam, P., Gerber, C., Haemmerli, A.-F., Guichard, S., Boukenna, M., Ross-Kaschitza, D., Lochner, M., Rougier, J.-S., Stahlberg, H., Abriel, H., Ni, D.. 2024-01-23. Identification of a Binding Site for Small Molecule Inhibitors Targeting Human TRPM4. https://doi.org/10.1101/2024.01.22.576650

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