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- EMDB-41134: TMEM16F, with Calcium and PIP2, no inhibitor -

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Basic information

Entry
Database: EMDB / ID: EMD-41134
TitleTMEM16F, with Calcium and PIP2, no inhibitor
Map dataTMEM16F, With Calcium and PIP2, No inhibitor, State B
Sample
  • Complex: 16F
    • Protein or peptide: Anoctamin-6
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: CALCIUM ION
KeywordsCalcium-activated / ion channels / lipid scramblases / MEMBRANE PROTEIN
Function / homology
Function and homology information


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 / bleb assembly / voltage-gated monoatomic ion channel activity / Stimuli-sensing channels / positive regulation of phagocytosis, engulfment / calcium-activated cation channel activity / positive regulation of monocyte chemotaxis / chloride transport / dendritic cell chemotaxis / phospholipid translocation / 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
Anoctamin, dimerisation domain / Anoctamin, dimerisation domain / Anoctamin / : / Calcium-activated chloride channel
Similarity search - Domain/homology
Biological speciesMus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsFeng S / Cheng Y
Funding support United States, 1 items
OrganizationGrant numberCountry
Howard Hughes Medical Institute (HHMI) United States
CitationJournal: Nat Commun / Year: 2023
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
DepositionJun 27, 2023-
Header (metadata) releaseSep 6, 2023-
Map releaseSep 6, 2023-
UpdateSep 6, 2023-
Current statusSep 6, 2023Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_41134.png

Downloads & links

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Map

FileDownload / File: emd_41134.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationTMEM16F, With Calcium and PIP2, No inhibitor, State B
Voxel sizeX=Y=Z: 0.839 Å
Density
Contour LevelBy AUTHOR: 0.271
Minimum - Maximum-2.2794132 - 3.473055
Average (Standard dev.)0.007246221 (±0.096625865)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 214.784 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: TMEM16F, With Calcium and PIP2, No inhibitor, State B, halfmap1

Fileemd_41134_half_map_1.map
AnnotationTMEM16F, With Calcium and PIP2, No inhibitor, State B, halfmap1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: TMEM16F, With Calcium and PIP2, No inhibitor, State B, halfmap2

Fileemd_41134_half_map_2.map
AnnotationTMEM16F, With Calcium and PIP2, No inhibitor, State B, halfmap2
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : 16F

EntireName: 16F
Components
  • Complex: 16F
    • Protein or peptide: Anoctamin-6
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: CALCIUM ION

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Supramolecule #1: 16F

SupramoleculeName: 16F / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Mus musculus (house mouse)

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Macromolecule #1: Anoctamin-6

MacromoleculeName: Anoctamin-6 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 95.924906 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: 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

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Macromolecule #2: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 2 / Number of copies: 6 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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Macromolecule #3: CALCIUM ION

MacromoleculeName: CALCIUM ION / type: ligand / ID: 3 / Number of copies: 3 / Formula: CA
Molecular weightTheoretical: 40.078 Da

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation statecell

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Sample preparation

BufferpH: 7.5
VitrificationCryogen name: ETHANE-PROPANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 45.8 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: DIFFRACTION / Nominal defocus max: 18.0 µm / Nominal defocus min: 10.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 32295
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION

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