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| Title | Temperature-dependent ligand relocation reveals plasticity of TRPM4 inhibition. |
|---|---|
| Journal, issue, pages | bioRxiv, Year 2026 |
| Publish date | May 14, 2026 |
Authors | Dominic Schneiter / Jean-Sébastien Rougier / Hugues Abriel / Henning Stahlberg / Babatunde Ekundayo |
| PubMed Abstract | Transient receptor potential melastatin 4 (TRPM4) is a Ca²⁺-activated cation channel whose pharmacology is shaped by its molecular environment. It remains poorly understood how temperature and ...Transient receptor potential melastatin 4 (TRPM4) is a Ca²⁺-activated cation channel whose pharmacology is shaped by its molecular environment. It remains poorly understood how temperature and membrane context influence inhibitor recognition. Here we combine cryo-electron microscopy of membrane-derived vesicles and detergent-solubilized TRPM4 to investigate lipid-associated architecture and binding of the potent anthranilic anilide inhibitor PBA. We find that membrane vesicles preserve a native-like paralipid environment and reveal lipid binding patterns highly similar to those observed in GDN, supporting detergent-solubilized TRPM4 as a structurally relevant system for ligand analysis. Strikingly, PBA occupies distinct binding pockets at 8□°C and 37□°C. At low temperature, PBA binds in a previously described inhibitor pocket formed by S3, S4, the S4-S5 linker and the TRP helix, whereas at physiological temperature it relocates to a distinct site within the S1-S4 domain proximal to the Ca²⁺ regulatory region. These findings reveal temperature-dependent plasticity in TRPM4 ligand recognition. |
External links | bioRxiv / PubMed:42182356 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 3.0 - 3.4 Å |
| Structure data | EMDB-57864, PDB-30kw: EMDB-57865, PDB-30kz: EMDB-57866, PDB-30la: EMDB-57879, PDB-30ld: |
| Chemicals | ![]() ChemComp-CLR: ![]() PDB-1j74: ![]() ChemComp-CA: |
| Source |
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Keywords | MEMBRANE PROTEIN / TRP channel / ion channel |
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