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- EMDB-48705: Cryo-EM Structure of Human Enterovirus D68 USA/IL/14-18952 -

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Basic information

Entry
Database: EMDB / ID: EMD-48705
TitleCryo-EM Structure of Human Enterovirus D68 USA/IL/14-18952
Map dataEnterovirus D68 USA/IL/14-18952 apo
Sample
  • Virus: enterovirus D68
    • Protein or peptide: viral protein 1
    • Protein or peptide: viral protein 2
    • Protein or peptide: viral protein 3
    • Protein or peptide: viral protein 4
  • Ligand: water
KeywordsVirus / Enterovirus
Function / homology
Function and homology information


symbiont-mediated suppression of cytoplasmic pattern recognition receptor signaling pathway / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of MDA-5 activity / protein sequestering activity / picornain 2A / symbiont-mediated suppression of host mRNA export from nucleus / symbiont genome entry into host cell via pore formation in plasma membrane / picornain 3C / T=pseudo3 icosahedral viral capsid / host cell cytoplasmic vesicle membrane / nucleoside-triphosphate phosphatase ...symbiont-mediated suppression of cytoplasmic pattern recognition receptor signaling pathway / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of MDA-5 activity / protein sequestering activity / picornain 2A / symbiont-mediated suppression of host mRNA export from nucleus / symbiont genome entry into host cell via pore formation in plasma membrane / picornain 3C / T=pseudo3 icosahedral viral capsid / host cell cytoplasmic vesicle membrane / nucleoside-triphosphate phosphatase / channel activity / symbiont-mediated suppression of host toll-like receptor signaling pathway / monoatomic ion transmembrane transport / symbiont-mediated suppression of host NF-kappaB cascade / RNA helicase activity / symbiont-mediated suppression of host innate immune response / endocytosis involved in viral entry into host cell / symbiont-mediated activation of host autophagy / RNA-directed RNA polymerase / cysteine-type endopeptidase activity / viral RNA genome replication / RNA-directed RNA polymerase activity / DNA-templated transcription / virion attachment to host cell / host cell nucleus / structural molecule activity / ATP hydrolysis activity / proteolysis / RNA binding / zinc ion binding / ATP binding / membrane / cytoplasm
Similarity search - Function
Picornavirus coat protein / Poliovirus 3A protein-like / Poliovirus 3A protein like / Picornavirus 2B protein / Poliovirus core protein 3a, soluble domain / Picornavirus 2B protein / Peptidase C3, picornavirus core protein 2A / Picornavirus core protein 2A / Picornavirus coat protein VP4 / Picornavirus coat protein (VP4) ...Picornavirus coat protein / Poliovirus 3A protein-like / Poliovirus 3A protein like / Picornavirus 2B protein / Poliovirus core protein 3a, soluble domain / Picornavirus 2B protein / Peptidase C3, picornavirus core protein 2A / Picornavirus core protein 2A / Picornavirus coat protein VP4 / Picornavirus coat protein (VP4) / Peptidase C3A/C3B, picornaviral / 3C cysteine protease (picornain 3C) / Picornavirales 3C/3C-like protease domain / Picornavirales 3C/3C-like protease domain profile. / Picornavirus capsid / picornavirus capsid protein / Helicase, superfamily 3, single-stranded RNA virus / Superfamily 3 helicase of positive ssRNA viruses domain profile. / Helicase, superfamily 3, single-stranded DNA/RNA virus / RNA helicase / Picornavirus/Calicivirus coat protein / Viral coat protein subunit / RNA-directed RNA polymerase, C-terminal domain / Viral RNA-dependent RNA polymerase / Reverse transcriptase/Diguanylate cyclase domain / RNA-directed RNA polymerase, catalytic domain / RdRp of positive ssRNA viruses catalytic domain profile. / ATPases associated with a variety of cellular activities / AAA+ ATPase domain / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan / DNA/RNA polymerase superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Genome polyprotein / Genome polyprotein / Genome polyprotein / Genome polyprotein
Similarity search - Component
Biological speciesenterovirus D68
Methodsingle particle reconstruction / cryo EM / Resolution: 2.0 Å
AuthorsXu L / Pintilie G / Varanese L / Carette JE / Chiu W
Funding support United States, 1 items
OrganizationGrant numberCountry
National Science Foundation (NSF, United States)DGE-1656518 United States
CitationJournal: Nature / Year: 2025
Title: MFSD6 is an entry receptor for enterovirus D68.
Authors: Lauren Varanese / Lily Xu / Christine E Peters / Grigore Pintilie / David S Roberts / Suyash Raj / Mengying Liu / Yaw Shin Ooi / Jonathan Diep / Wenjie Qiao / Christopher M Richards / Jeremy ...Authors: Lauren Varanese / Lily Xu / Christine E Peters / Grigore Pintilie / David S Roberts / Suyash Raj / Mengying Liu / Yaw Shin Ooi / Jonathan Diep / Wenjie Qiao / Christopher M Richards / Jeremy Callaway / Carolyn R Bertozzi / Sabrina Jabs / Erik de Vries / Frank J M van Kuppeveld / Claude M Nagamine / Wah Chiu / Jan E Carette /
Abstract: With the near eradication of poliovirus due to global vaccination campaigns, attention has shifted to other enteroviruses that can cause polio-like paralysis syndrome (now termed acute flaccid ...With the near eradication of poliovirus due to global vaccination campaigns, attention has shifted to other enteroviruses that can cause polio-like paralysis syndrome (now termed acute flaccid myelitis). In particular, enterovirus D68 (EV-D68) is believed to be the main driver of epidemic outbreaks of acute flaccid myelitis in recent years, yet not much is known about EV-D68 host interactions. EV-D68 is a respiratory virus but, in rare cases, can spread to the central nervous system to cause severe neuropathogenesis. Here we use genome-scale CRISPR screens to identify the poorly characterized multipass membrane transporter MFSD6 as a host entry factor for EV-D68. Knockout of MFSD6 expression abrogated EV-D68 infection in cell lines and primary cells corresponding to respiratory and neural cells. MFSD6 localized to the plasma membrane and was required for viral entry into host cells. MFSD6 bound directly to EV-D68 particles through its extracellular, third loop (L3). We determined the cryo-electron microscopy structure of EV-D68 in a complex with MFSD6 L3, revealing the interaction interface. A decoy receptor, engineered by fusing MFSD6 L3 to Fc, blocked EV-D68 infection of human primary lung epithelial cells and provided near-complete protection in a lethal mouse model of EV-D68 infection. Collectively, our results reveal MFSD6 as an entry receptor for EV-D68, and support the targeting of MFSD6 as a potential mechanism to combat infections by this emerging pathogen with pandemic potential.
History
DepositionJan 17, 2025-
Header (metadata) releaseMar 26, 2025-
Map releaseMar 26, 2025-
UpdateJun 11, 2025-
Current statusJun 11, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_48705.png

Downloads & links

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Map

FileDownload / File: emd_48705.map.gz / Format: CCP4 / Size: 1.4 GB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationEnterovirus D68 USA/IL/14-18952 apo
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesX (Sec.)Y (Row.)Z (Col.)
0.74 Å/pix.
x 720 pix.
= 534.96 Å		0.74 Å/pix.
x 720 pix.
= 534.96 Å		0.74 Å/pix.
x 720 pix.
= 534.96 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.743 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 5.0
Minimum - Maximum-4.3708944 - 16.894093000000002
Average (Standard dev.)-0.000000002932494 (±1.0)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderZYX
Origin000
Dimensions720720720
Spacing720720720
CellA=B=C: 534.95996 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Enterovirus D68 USA/IL/14-18952 apo half map A

Fileemd_48705_half_map_1.map
AnnotationEnterovirus D68 USA/IL/14-18952 apo half map A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Enterovirus D68 USA/IL/14-18952 apo half map B

Fileemd_48705_half_map_2.map
AnnotationEnterovirus D68 USA/IL/14-18952 apo half map B
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : enterovirus D68

EntireName: enterovirus D68
Components
  • Virus: enterovirus D68
    • Protein or peptide: viral protein 1
    • Protein or peptide: viral protein 2
    • Protein or peptide: viral protein 3
    • Protein or peptide: viral protein 4
  • Ligand: water

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Supramolecule #1: enterovirus D68

SupramoleculeName: enterovirus D68 / type: virus / ID: 1 / Parent: 0 / Macromolecule list: #1-#4
Details: Enterovirus D68 propagated and purified from infection of RD cells
NCBI-ID: 42789 / Sci species name: enterovirus D68 / Sci species strain: 14-18952 / Virus type: VIRION / Virus isolate: STRAIN / Virus enveloped: No / Virus empty: No
Host (natural)Organism: Homo sapiens (human)

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Macromolecule #1: viral protein 1

MacromoleculeName: viral protein 1 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO / EC number: picornain 2A
Source (natural)Organism: enterovirus D68 / Strain: USA/IL/14-18952
Molecular weightTheoretical: 32.854242 KDa
SequenceString: IESIIKTATD TVKSEINAEL GVVPSLNAVE TGATSNTEPE EAIQTRTVIN QHGVSETLVE NFLSRAALVS KRSFEYKDHT SSAAQTDKN FFKWTINTRS FVQLRRKLEL FTYLRFDAEI TILTTVAVNG SSNNTYVGLP DLTLQAMFVP TGALTPEKQD S FHWQSGSN ...String:
IESIIKTATD TVKSEINAEL GVVPSLNAVE TGATSNTEPE EAIQTRTVIN QHGVSETLVE NFLSRAALVS KRSFEYKDHT SSAAQTDKN FFKWTINTRS FVQLRRKLEL FTYLRFDAEI TILTTVAVNG SSNNTYVGLP DLTLQAMFVP TGALTPEKQD S FHWQSGSN ASVFFKISDP PARMTIPFMC INSAYSVFYD GFAGFEKSGL YGINPADTIG NLCVRIVNEH QPVGFTVTVR VY MKPKHIK AWAPRPPRTL PYMSIANANY KGKGRAPNAL NAIIGNRDSV KTMPHNIVTT

UniProtKB: Genome polyprotein

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Macromolecule #2: viral protein 2

MacromoleculeName: viral protein 2 / type: protein_or_peptide / ID: 2 / Details: Residues 1-11 deleted / Number of copies: 1 / Enantiomer: LEVO / EC number: picornain 2A
Source (natural)Organism: enterovirus D68 / Strain: USA/IL/14-18952
Molecular weightTheoretical: 26.527137 KDa
SequenceString: RVLQLKLGNS AIVTQEAANY CCAYGEWPNY LPDHEAVAID KPTQPETATD RFYTLRSVKW EAGSTGWWWK LPDALNNIGM FGQNVQHHY LYRSGFLIHV QCNATKFHQG ALLVVAIPEH QRGAHNTNTS PGFDDIMKGE EGGTFNHPYV LDDGTSLACA T IFPHQWIN ...String:
RVLQLKLGNS AIVTQEAANY CCAYGEWPNY LPDHEAVAID KPTQPETATD RFYTLRSVKW EAGSTGWWWK LPDALNNIGM FGQNVQHHY LYRSGFLIHV QCNATKFHQG ALLVVAIPEH QRGAHNTNTS PGFDDIMKGE EGGTFNHPYV LDDGTSLACA T IFPHQWIN LRTNNSATIV LPWMNAAPMD FPLRHNQWTL AIIPVVPLGT RTMSSMVPIT VSIAPMCCEF NGLRHAITQ

UniProtKB: Genome polyprotein

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Macromolecule #3: viral protein 3

MacromoleculeName: viral protein 3 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO / EC number: picornain 2A
Source (natural)Organism: enterovirus D68 / Strain: USA/IL/14-18952
Molecular weightTheoretical: 27.156867 KDa
SequenceString: GVPTYLLPGS GQFLTTDDHS SAPVLPCFNP TPEMHIPGQV RNMLEVVQVE SMMEINNTES AVGMERLKVD ISALTDVDQL LFNIPLDIQ LDGPLRNTLV GNISRYYTHW SGSLEMTFMF CGSFMATGKL ILCYTPPGGS CPTTRETAML GTHVVWDFGL Q SSVTLIIP ...String:
GVPTYLLPGS GQFLTTDDHS SAPVLPCFNP TPEMHIPGQV RNMLEVVQVE SMMEINNTES AVGMERLKVD ISALTDVDQL LFNIPLDIQ LDGPLRNTLV GNISRYYTHW SGSLEMTFMF CGSFMATGKL ILCYTPPGGS CPTTRETAML GTHVVWDFGL Q SSVTLIIP WISGSHYRMF NNDAKSTNAN VGYVTCFMQT NLIVPSESSD TCSLIGFIAA KDDFSLRLMR DSPDIGQLDH LH AAEAAYQ

UniProtKB: Genome polyprotein

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Macromolecule #4: viral protein 4

MacromoleculeName: viral protein 4 / type: protein_or_peptide / ID: 4 / Details: Residues 1-27 and 58-68 deleted / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: enterovirus D68 / Strain: USA/IL/14-18952
Molecular weightTheoretical: 3.401665 KDa
SequenceString:
QINFYKDSYA ASASKQDFSQ DPSKFTEPVV

UniProtKB: Genome polyprotein

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Macromolecule #5: water

MacromoleculeName: water / type: ligand / ID: 5 / Number of copies: 46 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER

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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

Concentration0.089 mg/mL
BufferpH: 8
Component:
ConcentrationFormulaName
20.0 mMTris-HClTris-HCl, pH 8.0
120.0 mMNaClsodium chloride
1.0 mMEDTAEDTA, pH 8.0

Details: 20 mM Tris-HCl (pH 8.0), 120 mM NaCl, and 1 mM EDTA (pH 8.0)
GridModel: Quantifoil / Material: COPPER / Mesh: 400 / Support film - Material: CARBON / Support film - topology: LACEY / Support film - Film thickness: 3 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 30 sec. / Pretreatment - Atmosphere: AIR
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277.15 K / Instrument: FEI VITROBOT MARK IV
Details: Freezing carried out with 4 s blot time, 1 s wait time..

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Number grids imaged: 1 / Number real images: 10400 / Average exposure time: 3.28 sec. / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: DARK FIELD / Cs: 2.7 mm / Nominal defocus max: 2.0 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: 23976
CTF correctionSoftware - Name: CTFFIND / Type: NONE
Startup modelType of model: INSILICO MODEL / In silico model: AlphaFold3 model of VP1, VP2, VP3, and VP4
Final reconstructionApplied symmetry - Point group: I (icosahedral) / Algorithm: FOURIER SPACE / Resolution.type: BY AUTHOR / Resolution: 2.0 Å / Resolution method: FSC 0.143 CUT-OFF / Software: (Name: RELION, cryoSPARC) / Number images used: 12930
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software: (Name: RELION, cryoSPARC)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software: (Name: RELION, cryoSPARC)
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelChain - Source name: AlphaFold / Chain - Initial model type: in silico model
DetailsInitial rigid fitting was done using Chimera and then ISOLDE was used for flexible fitting.
RefinementProtocol: FLEXIBLE FIT
Output model

PDB-9mwz:
Cryo-EM Structure of Human Enterovirus D68 USA/IL/14-18952

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