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Open data
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Basic information
Entry | ![]() | |||||||||
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Title | TMEM16F 1PBC | |||||||||
![]() | TMEM16F 1PBC | |||||||||
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![]() | Ca2+-activated ion channels / lipid scramblases / MEMBRANE PROTEIN | |||||||||
Function / homology | ![]() calcium activated phospholipid scrambling / calcium activated phosphatidylserine scrambling / calcium activated phosphatidylcholine scrambling / calcium activated galactosylceramide scrambling / positive regulation of potassium ion export across plasma membrane / purinergic nucleotide receptor signaling pathway / positive regulation of monoatomic ion transmembrane transport / phospholipid scramblase activity / negative regulation of cell volume / intracellularly calcium-gated chloride channel activity ...calcium activated phospholipid scrambling / calcium activated phosphatidylserine scrambling / calcium activated phosphatidylcholine scrambling / calcium activated galactosylceramide scrambling / positive regulation of potassium ion export across plasma membrane / purinergic nucleotide receptor signaling pathway / positive regulation of monoatomic ion transmembrane transport / phospholipid scramblase activity / negative regulation of cell volume / intracellularly calcium-gated chloride channel activity / bone mineralization involved in bone maturation / cholinergic synapse / plasma membrane phospholipid scrambling / voltage-gated monoatomic ion channel activity / bleb assembly / Stimuli-sensing channels / positive regulation of phagocytosis, engulfment / calcium-activated cation channel activity / positive regulation of monocyte chemotaxis / chloride transport / phospholipid translocation / dendritic cell chemotaxis / chloride channel activity / chloride channel complex / regulation of postsynaptic membrane potential / positive regulation of bone mineralization / chloride transmembrane transport / Neutrophil degranulation / synaptic membrane / establishment of localization in cell / calcium ion transmembrane transport / blood coagulation / positive regulation of apoptotic process / protein homodimerization activity / identical protein binding / metal ion binding / plasma membrane Similarity search - Function | |||||||||
Biological species | ![]() ![]() | |||||||||
Method | single particle reconstruction / Resolution: 3.12 Å | |||||||||
![]() | Wu H / Feng S / Cheng Y | |||||||||
Funding support | ![]()
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![]() | ![]() Title: Identification of a drug binding pocket in TMEM16F calcium-activated ion channel and lipid scramblase. Authors: Shengjie Feng / Cristina Puchades / Juyeon Ko / Hao Wu / Yifei Chen / Eric E Figueroa / Shuo Gu / Tina W Han / Brandon Ho / Tong Cheng / Junrui Li / Brian Shoichet / Yuh Nung Jan / Yifan Cheng / Lily Yeh Jan / ![]() Abstract: The dual functions of TMEM16F as Ca-activated ion channel and lipid scramblase raise intriguing questions regarding their molecular basis. Intrigued by the ability of the FDA-approved drug ...The dual functions of TMEM16F as Ca-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-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 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. | |||||||||
History |
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Structure visualization
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 59.7 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 15 KB 15 KB | Display Display | ![]() |
Images | ![]() | 48.3 KB | ||
Filedesc metadata | ![]() | 5.9 KB | ||
Others | ![]() ![]() | 59.3 MB 59.3 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 8sunMC ![]() 8surC ![]() 8tagC ![]() 8taiC ![]() 8talC M: atomic model generated by this map C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
File | ![]() | ||||||||||||||||||||
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Annotation | TMEM16F 1PBC | ||||||||||||||||||||
Voxel size | X=Y=Z: 0.839 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: TMEM16F 1PBC half1
File | emd_40768_half_map_1.map | ||||||||||||
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Annotation | TMEM16F 1PBC half1 | ||||||||||||
Projections & Slices |
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Density Histograms |
-Half map: TMEM16F 1PBC half2
File | emd_40768_half_map_2.map | ||||||||||||
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Annotation | TMEM16F 1PBC half2 | ||||||||||||
Projections & Slices |
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Density Histograms |
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Sample components
-Entire : 16F
Entire | Name: 16F |
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Components |
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-Supramolecule #1: 16F
Supramolecule | Name: 16F / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1 |
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Source (natural) | Organism: ![]() ![]() |
-Macromolecule #1: Anoctamin-6
Macromolecule | Name: Anoctamin-6 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() ![]() |
Molecular weight | Theoretical: 95.924906 KDa |
Recombinant expression | Organism: ![]() |
Sequence | String: FEEFNGKPDS LFFTDGQRRI DFILVYEDES KKENNKKGTN EKQKRKRQAY ESNLICHGLQ LEATRSVSDD KLVFVKVHAP WEVLCYYAE IMHIKLPLKP NDLKTRSPFG NLNWFTKVLR VNESVIKPEQ EFFTAPFEKS RMNDFYILDR DSFFNPATRS R IVYFILSR ...String: FEEFNGKPDS LFFTDGQRRI DFILVYEDES KKENNKKGTN EKQKRKRQAY ESNLICHGLQ LEATRSVSDD KLVFVKVHAP WEVLCYYAE IMHIKLPLKP NDLKTRSPFG NLNWFTKVLR VNESVIKPEQ EFFTAPFEKS RMNDFYILDR DSFFNPATRS R IVYFILSR VKYQVMNNVN KFGINRLVSS GIYKAAFPLH DCRFNYESED ISCPSERYLL YREWAHPRSI YKKQPLDLIR KY YGEKIGI YFAWLGYYTQ MLLLAAVVGV ACFLYGYLDQ DNCTWSKEVC DPDIGGQILM CPQCDRLCPF WRLNITCESS KKL CIFDSF GTLIFAVFMG VWVTLFLEFW KRRQAELEYE WDTVELQQEE QARPEYEAQC NHVVINEITQ EEERIPFTTC GKCI RVTLC ASAVFFWILL IIASVIGIIV YRLSVFIVFS TTLPKNPNGT DPIQKYLTPQ MATSITASII SFIIIMILNT IYEKV AIMI TNFELPRTQT DYENSLTMKM FLFQFVNYYS SCFYIAFFKG KFVGYPGDPV YLLGKYRSEE CDPGGCLLEL TTQLTI IMG GKAIWNNIQE VLLPWVMNLI GRYKRVSGSE KITPRWEQDY HLQPMGKLGL FYEYLEMIIQ FGFVTLFVAS FPLAPLL AL VNNILEIRVD AWKLTTQFRR MVPEKAQDIG AWQPIMQGIA ILAVVTNAMI IAFTSDMIPR LVYYWSFSIP PYGDHTYY T MDGYINNTLS VFNITDFKNT DKENPYIGLG NYTLCRYRDF RNPPGHPQEY KHNIYYWHVI AAKLAFIIVM EHIIYSVKF FISYAIPDVS KITKSKIKRE UniProtKB: Anoctamin-6 |
-Macromolecule #2: 2-acetamido-2-deoxy-beta-D-glucopyranose
Macromolecule | Name: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 2 / Number of copies: 6 / Formula: NAG |
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Molecular weight | Theoretical: 221.208 Da |
Chemical component information | ![]() ChemComp-NAG: |
-Macromolecule #3: CALCIUM ION
Macromolecule | Name: CALCIUM ION / type: ligand / ID: 3 / Number of copies: 3 / Formula: CA |
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Molecular weight | Theoretical: 40.078 Da |
-Macromolecule #4: 1-Hydroxy-3-(trifluoromethyl)pyrido[1,2-a]benzimidazole-4-carbonitrile
Macromolecule | Name: 1-Hydroxy-3-(trifluoromethyl)pyrido[1,2-a]benzimidazole-4-carbonitrile type: ligand / ID: 4 / Number of copies: 1 / Formula: JRF |
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Molecular weight | Theoretical: 277.201 Da |
Chemical component information | ![]() ChemComp-JRF: |
-Experimental details
-Structure determination
![]() | single particle reconstruction |
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Aggregation state | cell |
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Sample preparation
Buffer | pH: 7.5 |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K3 (6k x 4k) / Average electron dose: 66.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Illumination mode: SPOT SCAN / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.0 µm |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Image processing
Startup model | Type of model: NONE |
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Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 3.12 Å / Number images used: 186223 |
Initial angle assignment | Type: ANGULAR RECONSTITUTION |
Final angle assignment | Type: ANGULAR RECONSTITUTION |