30KW

Human Trpm4 at 8 degrees Celsius

Summary for 30KW

• Entry DOI: 10.2210/pdb30kw/pdb
• EMDB information: 57864
• Descriptor: Transient receptor potential cation channel subfamily M member 4, CHOLESTEROL (2 entities in total)
• Functional Keywords: trp channel, ion channel, membrane protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 545559.02

Authors

Schneiter, D.,Ekundayo, B.E.,Stahlberg, H.,Abriel, H. (deposition date: 2026-05-01, release date: 2026-06-03)

Primary citation

Schneiter, D.,Rougier, J.S.,Abriel, H.,Stahlberg, H.,Ekundayo, B.
Temperature-dependent ligand relocation reveals plasticity of TRPM4 inhibition.
Biorxiv, 2026

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 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.

PubMed: 42182356
DOI: 10.64898/2026.05.13.724805

Experimental method

ELECTRON MICROSCOPY (3.1 Å)