8tal | pdb_00008tal

TMEM16F, with Calcium and PIP2, no inhibitor, Cl1

spinqualitylabelsall models 8tal, resolution 3.20Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8tal is a 2 chain structure with sequence from Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 3.2Å Ligands: CA, NAG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function ANO6_MOUSE Small-conductance calcium-activated nonselective cation (SCAN) channel which acts as a regulator of phospholipid scrambling in platelets, osteoblasts and fetal thymocytes. Phospholipid scrambling results in surface exposure of phosphatidylserine which in platelets is essential to trigger the clotting system whereas in osteoblasts is essential for the deposition of hydroxyapatite during bone mineralization. Has calcium-dependent phospholipid scramblase activity; scrambles phosphatidylserine, phosphatidylcholine and galactosylceramide. Can generate outwardly rectifying chloride channel currents in airway epithelial cells and Jurkat T lymphocytes. Publication Abstract from PubMed The dual functions of TMEM16F as Ca(2+)-activated ion channel and lipid scramblase raise intriguing questions regarding their molecular basis. Intrigued by the ability of the FDA-approved drug niclosamide to inhibit TMEM16F-dependent syncytia formation induced by SARS-CoV-2, we examined cryo-EM structures of TMEM16F with or without bound niclosamide or 1PBC, a known blocker of TMEM16A Ca(2+)-activated Cl(-) channel. Here, we report evidence for a lipid scrambling pathway along a groove harboring a lipid trail outside the ion permeation pore. This groove contains the binding pocket for niclosamide and 1PBC. Mutations of two residues in this groove specifically affect lipid scrambling. Whereas mutations of some residues in the binding pocket of niclosamide and 1PBC reduce their inhibition of TMEM16F-mediated Ca(2+) influx and PS exposure, other mutations preferentially affect the ability of niclosamide and/or 1PBC to inhibit TMEM16F-mediated PS exposure, providing further support for separate pathways for ion permeation and lipid scrambling. Identification of a drug binding pocket in TMEM16F calcium-activated ion channel and lipid scramblase.,Feng S, Puchades C, Ko J, Wu H, Chen Y, Figueroa EE, Gu S, Han TW, Ho B, Cheng T, Li J, Shoichet B, Jan YN, Cheng Y, Jan LY Nat Commun. 2023 Aug 12;14(1):4874. doi: 10.1038/s41467-023-40410-x. PMID:37573365 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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