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

Ekundayo, Babatunde; Arullampalam, Prakash; Gerber, Christian E.; Hämmerli, Anne-Flore; Guichard, Sabrina; Boukenna, Mey; Ross, Daniela; Lochner, Martin; Rougier, Jean-Sébastien; Stahlberg, Henning; Abriel, Hugues; Ni, Dongchun (23 January 2024). Identification of a Binding Site for Small Molecule Inhibitors Targeting Human TRPM4 (bioRxiv). Cold Spring Harbor Laboratory 10.1101/2024.01.22.576650

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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 his information is crucial for drug development targeting TRPM4. We determined the cryo-EM structures of full-length human TRPM4 embedded in native lipid nanodiscs in an unbound, a state bound to NBA, and a new anthranilic acid derivative known as IBA-bound state. 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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