Identification of a binding site for small molecule inhibitors targeting human TRPM4
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...
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56131-2 |
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| author | 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 Dongchun Ni |
| author_facet | 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 Dongchun Ni |
| author_sort | Babatunde Ekundayo |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-e77da6ebfc2244aa9cdf422201597e12 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-e77da6ebfc2244aa9cdf422201597e122025-01-19T12:30:05ZengNature PortfolioNature Communications2041-17232025-01-0116111410.1038/s41467-025-56131-2Identification of a binding site for small molecule inhibitors targeting human TRPM4Babatunde Ekundayo0Prakash Arullampalam1Christian E. Gerber2Anne-Flore Hämmerli3Sabrina Guichard4Mey Boukenna5Daniela Ross-Kaschitza6Martin Lochner7Jean-Sebastien Rougier8Henning Stahlberg9Hugues Abriel10Dongchun Ni11Laboratory of Biological Electron Microscopy, IPHYS, SB, EPFL, and Dept. Fundamental Microbiology, Faculty of Biology and Medicine, UNIL, Cubotron, Rt. de la SorgeInstitute of Biochemistry and Molecular Medicine and Swiss National Centre of Competence in Research TransCure, University of BernInstitute of Biochemistry and Molecular Medicine and Swiss National Centre of Competence in Research TransCure, University of BernInstitute of Biochemistry and Molecular Medicine and Swiss National Centre of Competence in Research TransCure, University of BernInstitute of Biochemistry and Molecular Medicine and Swiss National Centre of Competence in Research TransCure, University of BernInstitute of Biochemistry and Molecular Medicine and Swiss National Centre of Competence in Research TransCure, University of BernInstitute of Biochemistry and Molecular Medicine and Swiss National Centre of Competence in Research TransCure, University of BernInstitute of Biochemistry and Molecular Medicine and Swiss National Centre of Competence in Research TransCure, University of BernInstitute of Biochemistry and Molecular Medicine and Swiss National Centre of Competence in Research TransCure, University of BernLaboratory of Biological Electron Microscopy, IPHYS, SB, EPFL, and Dept. Fundamental Microbiology, Faculty of Biology and Medicine, UNIL, Cubotron, Rt. de la SorgeInstitute of Biochemistry and Molecular Medicine and Swiss National Centre of Competence in Research TransCure, University of BernLaboratory of Biological Electron Microscopy, IPHYS, SB, EPFL, and Dept. Fundamental Microbiology, Faculty of Biology and Medicine, UNIL, Cubotron, Rt. de la SorgeAbstract 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.https://doi.org/10.1038/s41467-025-56131-2 |
| spellingShingle | 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 Dongchun Ni Identification of a binding site for small molecule inhibitors targeting human TRPM4 Nature Communications |
| title | Identification of a binding site for small molecule inhibitors targeting human TRPM4 |
| title_full | Identification of a binding site for small molecule inhibitors targeting human TRPM4 |
| title_fullStr | Identification of a binding site for small molecule inhibitors targeting human TRPM4 |
| title_full_unstemmed | Identification of a binding site for small molecule inhibitors targeting human TRPM4 |
| title_short | Identification of a binding site for small molecule inhibitors targeting human TRPM4 |
| title_sort | identification of a binding site for small molecule inhibitors targeting human trpm4 |
| url | https://doi.org/10.1038/s41467-025-56131-2 |
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