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- EMDB-48323: Structure of the IFIT2-IFIT3 heterodimer from Mus musculus -

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Basic information

Entry
Database: EMDB / ID: EMD-48323
TitleStructure of the IFIT2-IFIT3 heterodimer from Mus musculus
Map dataSharpened map of mm IFIT2-3
Sample
  • Complex: Dimeric complex of Interferon-induced protein with tetratricopeptide repeats 2 and Interferon-induced protein with tetratricopeptide repeats 3
    • Protein or peptide: Interferon-induced protein with tetratricopeptide repeats 2
    • Protein or peptide: Interferon-induced protein with tetratricopeptide repeats 3
Keywordsinnate immune recognition / interferon-induced proteins / non-self nucleic acids / ANTIVIRAL PROTEIN
Function / homology
Function and homology information


response to stilbenoid / cellular response to interferon-alpha / cellular response to interferon-beta / antiviral innate immune response / response to bacterium / response to virus / defense response to virus / positive regulation of apoptotic process / negative regulation of cell population proliferation / innate immune response ...response to stilbenoid / cellular response to interferon-alpha / cellular response to interferon-beta / antiviral innate immune response / response to bacterium / response to virus / defense response to virus / positive regulation of apoptotic process / negative regulation of cell population proliferation / innate immune response / apoptotic process / negative regulation of apoptotic process / endoplasmic reticulum / mitochondrion / RNA binding / cytoplasm
Similarity search - Function
Tetratricopeptide repeat / Tetratricopeptide repeat / TPR repeat region circular profile. / TPR repeat profile. / Tetratricopeptide repeats / Tetratricopeptide repeat / Tetratricopeptide-like helical domain superfamily
Similarity search - Domain/homology
Interferon-induced protein with tetratricopeptide repeats 2 / Interferon-induced protein with tetratricopeptide repeats 3
Similarity search - Component
Biological speciesMus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.22 Å
AuthorsGlasner DR / Todd C / Cook BD / DUrso A / Khosla S / Estrada E / Wagner J / Bartels MD / Ford P / Prych J ...Glasner DR / Todd C / Cook BD / DUrso A / Khosla S / Estrada E / Wagner J / Bartels MD / Ford P / Prych J / Hatch K / Yee BA / Ego KM / Liang Q / Holland SR / Case JB / Corbett KD / Diamond MS / Yeo GW / Herzik Jr MA / Van Nostrand EL / Daugherty MD
Funding support United States, 5 items
OrganizationGrant numberCountry
National Institutes of Health/National Human Genome Research Institute (NIH/NHGRI)U24 HG009889 United States
National Institutes of Health/National Institute of Mental Health (NIH/NIMH)RF1 MH126719 United States
National Institutes of Health/National Human Genome Research Institute (NIH/NHGRI)R01 HG011864 United States
National Institutes of Health/National Human Genome Research Institute (NIH/NHGRI)National Human Genome Research Institute United States
National Institutes of Health/National Human Genome Research Institute (NIH/NHGRI)U24 HG011735 United States
CitationJournal: bioRxiv / Year: 2025
Title: Short 5' UTRs serve as a marker for viral mRNA translation inhibition by the IFIT2-IFIT3 antiviral complex.
Authors: Dustin R Glasner / Candace Todd / Brian Cook / Agustina D'Urso / Shivani Khosla / Elena Estrada / Jaxon D Wagner / Mason D Bartels / Pierce Ford / Jordan Prych / Katie Hatch / Brian A Yee / ...Authors: Dustin R Glasner / Candace Todd / Brian Cook / Agustina D'Urso / Shivani Khosla / Elena Estrada / Jaxon D Wagner / Mason D Bartels / Pierce Ford / Jordan Prych / Katie Hatch / Brian A Yee / Kaori M Ego / Qishan Liang / Sarah R Holland / James Brett Case / Kevin D Corbett / Michael S Diamond / Gene W Yeo / Mark A Herzik / Eric L Van Nostrand / Matthew D Daugherty /
Abstract: Recognition of "non-self" nucleic acids, including cytoplasmic dsDNA, dsRNA, or mRNAs lacking proper 5' cap structures, is critical for the innate immune response to viruses. Here, we demonstrate ...Recognition of "non-self" nucleic acids, including cytoplasmic dsDNA, dsRNA, or mRNAs lacking proper 5' cap structures, is critical for the innate immune response to viruses. Here, we demonstrate that short 5' untranslated regions (UTRs), a characteristic of many viral mRNAs, can also serve as a molecular pattern for innate immune recognition via the interferon-induced proteins IFIT2 and IFIT3. The IFIT2-IFIT3 heterodimer, formed through an intricate domain swap structure resolved by cryo-EM, mediates viral mRNA 5' end recognition, translation inhibition, and ultimately antiviral activity. Critically, 5' UTR lengths <50 nucleotides are necessary and sufficient to sensitize an mRNA to translation inhibition by the IFIT2-IFIT3 complex. Accordingly, diverse viruses whose mRNAs contain short 5' UTRs, such as vesicular stomatitis virus and parainfluenza virus 3, are sensitive to IFIT2-IFIT3-mediated antiviral activity. Our work thus reveals a pattern of antiviral nucleic acid immune recognition that takes advantage of the inherent constraints on viral genome size.
History
DepositionDec 16, 2024-
Header (metadata) releaseMar 12, 2025-
Map releaseMar 12, 2025-
UpdateMar 12, 2025-
Current statusMar 12, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_48323.png

Downloads & links

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Map

FileDownload / File: emd_48323.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationSharpened map of mm IFIT2-3
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.85 Å/pix.
x 384 pix.
= 327.936 Å		0.85 Å/pix.
x 384 pix.
= 327.936 Å		0.85 Å/pix.
x 384 pix.
= 327.936 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.854 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.1
Minimum - Maximum-0.38876384 - 0.7516551
Average (Standard dev.)0.000013081694 (±0.010886232)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions384384384
Spacing384384384
CellA=B=C: 327.93597 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_48323_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Additional map: Unsharpened map of mm IFIT2-3

Fileemd_48323_additional_1.map
AnnotationUnsharpened map of mm IFIT2-3
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map B of mm IFIT2-3

Fileemd_48323_half_map_1.map
AnnotationHalf map B of mm IFIT2-3
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map A of mm IFIT2-3

Fileemd_48323_half_map_2.map
AnnotationHalf map A of mm IFIT2-3
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Dimeric complex of Interferon-induced protein with tetratricopept...

EntireName: Dimeric complex of Interferon-induced protein with tetratricopeptide repeats 2 and Interferon-induced protein with tetratricopeptide repeats 3
Components
  • Complex: Dimeric complex of Interferon-induced protein with tetratricopeptide repeats 2 and Interferon-induced protein with tetratricopeptide repeats 3
    • Protein or peptide: Interferon-induced protein with tetratricopeptide repeats 2
    • Protein or peptide: Interferon-induced protein with tetratricopeptide repeats 3

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Supramolecule #1: Dimeric complex of Interferon-induced protein with tetratricopept...

SupramoleculeName: Dimeric complex of Interferon-induced protein with tetratricopeptide repeats 2 and Interferon-induced protein with tetratricopeptide repeats 3
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 102.22558 KDa

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Macromolecule #1: Interferon-induced protein with tetratricopeptide repeats 2

MacromoleculeName: Interferon-induced protein with tetratricopeptide repeats 2
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 51.702301 KDa
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString: ESLVCNLRQL KCHFTWNLIA EDESLDEFED RVFNKDEFQN SEFKATMCNI LAYVKHCRGL NEAALQCLGE AEGFIQQQHP DQVEIRSLV TWGNYAWVYY HMGQFSKAQA YLDKVKQVCK KFSSPYRIEN PALDCEEGWA RLKCTKNQNE RVKVCFQKAL E KDPKNPEF ...String:
ESLVCNLRQL KCHFTWNLIA EDESLDEFED RVFNKDEFQN SEFKATMCNI LAYVKHCRGL NEAALQCLGE AEGFIQQQHP DQVEIRSLV TWGNYAWVYY HMGQFSKAQA YLDKVKQVCK KFSSPYRIEN PALDCEEGWA RLKCTKNQNE RVKVCFQKAL E KDPKNPEF TSGWAIANYR LDDWPARNYC IDSLEQAIQL SPDNTYVKVL LALKLDAVHK NQAMALVEEA LKKDPSAIDT LL RAARFYC KVYDTDRAIQ LLRKALEKLP NNAYVHYYMG CCYRSKVHHM LNRREMVFSG DRKKLEELIQ LAVNHLRKAE EIK EMLEYS CSFLADLYII AKKYDEADYY FQKELSKDLP PGPKQLLHLR YGNFQFFQMK RQDKAIYHYM EGVKIKKKTI PQKK MREKL QRIALRRLHE DESDSEALHI LAFLQENGGG QQADK

UniProtKB: Interferon-induced protein with tetratricopeptide repeats 2

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Macromolecule #2: Interferon-induced protein with tetratricopeptide repeats 3

MacromoleculeName: Interferon-induced protein with tetratricopeptide repeats 3
type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 44.740059 KDa
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString: SLEAILPQLK CHFTWNLFRE GSMSSHMEDR VCNQVEHLNS EEKATMYDLL AYIKHLDGES KAALECLGQA EDLRKSEHND QSEIRRLVT WGNYAWIYYH MGRLSEAQAY VDKVRQVCQK FANPYSMECP ELECEEGWTR LKCGRNERAK MCFEKALEEK P KDPECSSG ...String:
SLEAILPQLK CHFTWNLFRE GSMSSHMEDR VCNQVEHLNS EEKATMYDLL AYIKHLDGES KAALECLGQA EDLRKSEHND QSEIRRLVT WGNYAWIYYH MGRLSEAQAY VDKVRQVCQK FANPYSMECP ELECEEGWTR LKCGRNERAK MCFEKALEEK P KDPECSSG MAIAMFRLEE KPEKQFSVDA LKQAMELNPQ NQYLKVLLAL KLLRMGEEAE GERLIKDALG KAPNQTDVLQ KA AQFYKKK GNLDRAIELL GKALRSTVNN SPLYSLVMCR YREILEQLQN KGDADSSERR QRMAELRRLT MEFMQKTLQR RRS PLNSYS DLIDFPEVER CYQMVISKES PDVEEEDLYE RYCNLQEYHR KSEDLAALEC LLQFPR

UniProtKB: Interferon-induced protein with tetratricopeptide repeats 3

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration3 mg/mL
BufferpH: 7.5
Component:
ConcentrationFormulaName
20.0 mMNH2C(CH2OH)3HClTris-HCl
150.0 mMNaClSodium Chloride
1.0 mMC4H10O2S2Dithiothreitol
GridModel: UltrAuFoil R1.2/1.3 / Material: COPPER / Mesh: 300 / Support film - Material: GOLD / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 10 sec.
VitrificationCryogen name: ETHANE-PROPANE / Chamber humidity: 90 % / Chamber temperature: 277.15 K / Instrument: HOMEMADE PLUNGER

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Electron microscopy

MicroscopeTFS KRIOS
Specialist opticsEnergy filter - Name: GIF Bioquantum / Energy filter - Slit width: 20 eV
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Number grids imaged: 1 / Number real images: 2355 / Average electron dose: 65.0 e/Å2
Details: Images were collected on a Gatan K2 summit detector equipped with a Gatan BioContinuum energy filter
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.0 µm / Nominal magnification: 165000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 268606
Startup modelType of model: OTHER / Details: Ab-initio reconstruction
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Algorithm: FOURIER SPACE / Resolution.type: BY AUTHOR / Resolution: 3.22 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 80378
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC / Details: Ab-initio reconstruction
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: RIGID BODY FIT / Overall B value: 107.7
Output model

PDB-9mk9:
Structure of the IFIT2-IFIT3 heterodimer from Mus musculus

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