9y2a

Cryo-EM structure of the human TRPM4 channel in complex with calcium and DAB at 37 degrees Celsius

spinqualitylabelsall models 9y2a, resolution 3.30Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9y2a is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 3.3Å Ligands: A1CR0, CA Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Imbalance in intestinal fluid homeostasis leads to nutrient malabsorption, intestinal tissue destruction, and systemic inflammation. Transient receptor potential melastatin 4 (TRPM4) is a calcium-activated, non-selective monovalent cation channel converting chemical signals (Ca(2+)) into electrical signals (membrane depolarization). Here, we show the TRPM4 channel as a direct target of bisacodyl (BIC), a widely used clinical drug for chronic constipation management, and its active metabolite, deacetyl bisacodyl (DAB). DAB-induced laxative effects are abolished in global and intestinal epithelium-specific TRPM4-knockout mice, establishing the essential role of TRPM4 in intestinal fluid regulation. Furthermore, our structural work reveals DAB bound to an uncharacterized pocket, marking it as a non-Ca(2+) TRPM4 agonist and unveiling a noncanonical Ca(2+)-independent activation mechanism. Additionally, we delineate a signaling axis, TRPM4 --> VGCC/NCX --> ANO1, that governs ion homeostasis in the epithelium. Together, these findings establish TRPM4 as a key regulator of intestinal fluid balance and reveal its noncanonical calcium-independent activation as a therapeutic strategy for constipation. Noncanonical calcium-independent TRPM4 activation governs intestinal fluid homeostasis.,Liu Y, Hu J, Xue C, Huang W, Ievleva S, Lu W, Du J, Cao Z Nat Commun. 2026 Jan 8;17(1):1253. doi: 10.1038/s41467-025-68014-7. PMID:41507162 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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