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- EMDB-6854: Structure of JEV-2F2 Fab complex -

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Basic information

Entry
Database: EMDB / ID: EMD-6854
TitleStructure of JEV-2F2 Fab complex
Map data
Sample
  • Complex: Complex of JEV with 2F2 Fab
    • Protein or peptide: JEV E protein
    • Protein or peptide: JEV M protein
    • Protein or peptide: 2F2 light chain
    • Protein or peptide: 2F2 heavy chain
KeywordsFlaviviruses / Viral encephalitis / neutralizing monoclonal antibodies / structural analysis / VIRUS
Function / homology
Function and homology information


flavivirin / symbiont-mediated suppression of host JAK-STAT cascade via inhibition of host TYK2 activity / symbiont-mediated suppression of host JAK-STAT cascade via inhibition of STAT2 activity / symbiont-mediated suppression of host JAK-STAT cascade via inhibition of STAT1 activity / double-stranded RNA binding / nucleoside-triphosphate phosphatase / viral capsid / mRNA (guanine-N7)-methyltransferase / methyltransferase cap1 / clathrin-dependent endocytosis of virus by host cell ...flavivirin / symbiont-mediated suppression of host JAK-STAT cascade via inhibition of host TYK2 activity / symbiont-mediated suppression of host JAK-STAT cascade via inhibition of STAT2 activity / symbiont-mediated suppression of host JAK-STAT cascade via inhibition of STAT1 activity / double-stranded RNA binding / nucleoside-triphosphate phosphatase / viral capsid / mRNA (guanine-N7)-methyltransferase / methyltransferase cap1 / clathrin-dependent endocytosis of virus by host cell / mRNA (nucleoside-2'-O-)-methyltransferase activity / mRNA 5'-cap (guanine-N7-)-methyltransferase activity / host cell surface / RNA helicase activity / host cell perinuclear region of cytoplasm / protein dimerization activity / host cell endoplasmic reticulum membrane / RNA helicase / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / induction by virus of host autophagy / RNA-directed RNA polymerase / viral translational frameshifting / viral RNA genome replication / serine-type endopeptidase activity / RNA-dependent RNA polymerase activity / virus-mediated perturbation of host defense response / fusion of virus membrane with host endosome membrane / viral envelope / host cell nucleus / virion attachment to host cell / structural molecule activity / virion membrane / ATP hydrolysis activity / proteolysis / extracellular region / ATP binding / membrane / metal ion binding
Similarity search - Function
Flavivirus capsid protein C superfamily / Flavivirus non-structural protein NS2B / Genome polyprotein, Flavivirus / : / mRNA cap 0/1 methyltransferase / mRNA cap 0 and cap 1 methyltransferase (EC 2.1.1.56 and EC 2.1.1.57) domain profile. / Flavivirus non-structural protein NS4A / Flavivirus non-structural protein NS2B / Flavivirus capsid protein C / Flavivirus non-structural protein NS4B ...Flavivirus capsid protein C superfamily / Flavivirus non-structural protein NS2B / Genome polyprotein, Flavivirus / : / mRNA cap 0/1 methyltransferase / mRNA cap 0 and cap 1 methyltransferase (EC 2.1.1.56 and EC 2.1.1.57) domain profile. / Flavivirus non-structural protein NS4A / Flavivirus non-structural protein NS2B / Flavivirus capsid protein C / Flavivirus non-structural protein NS4B / Flavivirus capsid protein C / Flavivirus non-structural protein NS4B / Flavivirus non-structural protein NS4A / Flavivirus NS2B domain profile. / Flavivirus non-structural protein NS2A / Flavivirus non-structural protein NS2A / RNA-directed RNA polymerase, thumb domain, Flavivirus / Flavivirus RNA-directed RNA polymerase, thumb domain / Flavivirus NS3, petidase S7 / Peptidase S7, Flavivirus NS3 serine protease / Flavivirus NS3 protease (NS3pro) domain profile. / RNA-directed RNA polymerase, flavivirus / Flavivirus RNA-directed RNA polymerase, fingers and palm domains / Flavivirus non-structural Protein NS1 / Flavivirus non-structural protein NS1 / Envelope glycoprotein M, flavivirus / Envelope glycoprotein M superfamily, flavivirus / Flavivirus polyprotein propeptide / Flavivirus polyprotein propeptide superfamily / Flavivirus polyprotein propeptide / Flavivirus envelope glycoprotein M / Flavivirus envelope glycoprotein E, stem/anchor domain / Flavivirus envelope glycoprotein E, Stem/Anchor domain / Flavivirus envelope glycoprotein E, Stem/Anchor domain superfamily / Flavivirus glycoprotein E, immunoglobulin-like domain / : / Flavivirus glycoprotein central and dimerisation domain / Flaviviral glycoprotein E, central domain, subdomain 1 / Flaviviral glycoprotein E, central domain, subdomain 2 / Flavivirus NS3 helicase, C-terminal helical domain / Flavivirus glycoprotein, immunoglobulin-like domain / Flavivirus glycoprotein, central and dimerisation domains / Ribosomal RNA methyltransferase, FtsJ domain / FtsJ-like methyltransferase / Flavivirus/Alphavirus glycoprotein, immunoglobulin-like domain superfamily / Flavivirus glycoprotein, central and dimerisation domain superfamily / Flaviviral glycoprotein E, dimerisation domain / DEAD box, Flavivirus / Flavivirus DEAD domain / helicase superfamily c-terminal domain / Immunoglobulin E-set / Superfamilies 1 and 2 helicase C-terminal domain profile. / Superfamilies 1 and 2 helicase ATP-binding type-1 domain profile. / DEAD-like helicases superfamily / Helicase, C-terminal / Helicase superfamily 1/2, ATP-binding domain / RNA-directed RNA polymerase, catalytic domain / RdRp of positive ssRNA viruses catalytic domain profile. / S-adenosyl-L-methionine-dependent methyltransferase superfamily / Peptidase S1, PA clan / DNA/RNA polymerase superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Genome polyprotein / Genome polyprotein
Similarity search - Component
Biological speciesJapanese encephalitis virus / Mus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.7 Å
AuthorsQiu X / Lei Y
Funding support China, 1 items
OrganizationGrant numberCountry
National Key Research and Development Program of China2016YFC1200400 China
CitationJournal: Nat Microbiol / Year: 2018
Title: Structural basis for neutralization of Japanese encephalitis virus by two potent therapeutic antibodies.
Authors: Xiaodi Qiu / Yingfeng Lei / Pan Yang / Qiang Gao / Nan Wang / Lei Cao / Shuai Yuan / Xiaofang Huang / Yongqiang Deng / Wenyu Ma / Tianbing Ding / Fanglin Zhang / Xingan Wu / Junjie Hu / Shan- ...Authors: Xiaodi Qiu / Yingfeng Lei / Pan Yang / Qiang Gao / Nan Wang / Lei Cao / Shuai Yuan / Xiaofang Huang / Yongqiang Deng / Wenyu Ma / Tianbing Ding / Fanglin Zhang / Xingan Wu / Junjie Hu / Shan-Lu Liu / Chengfeng Qin / Xiangxi Wang / Zhikai Xu / Zihe Rao /
Abstract: Japanese encephalitis virus (JEV), closely related to dengue, Zika, yellow fever and West Nile viruses, remains neglected and not well characterized . JEV is the leading causative agent of ...Japanese encephalitis virus (JEV), closely related to dengue, Zika, yellow fever and West Nile viruses, remains neglected and not well characterized . JEV is the leading causative agent of encephalitis, and is responsible for thousands of deaths each year in Asia. Humoral immunity is essential for protecting against flavivirus infections and passive immunization has been demonstrated to be effective in curing disease. Here, we demonstrate that JEV-specific monoclonal antibodies, 2F2 and 2H4, block attachment of the virus to its receptor and also prevent fusion of the virus. Neutralization of JEV by these antibodies is exceptionally potent and confers clear therapeutic benefit in mouse models. A single 20 μg dose of these antibodies resulted in 100% survival and complete clearance of JEV from the brains of mice. The 4.7 Å and 4.6 Å resolution cryo-electron microscopy structures of JEV-2F2-Fab and JEV-2H4-Fab complexes, together with the crystal structure of 2H4 Fab and our recent near-atomic structure of JEV , unveil the nature and location of epitopes targeted by the antibodies. Both 2F2 and 2H4 Fabs bind quaternary epitopes that span across three adjacent envelope proteins. Our results provide a structural and molecular basis for the application of 2F2 and 2H4 to treat JEV infection.
History
DepositionNov 29, 2017-
Header (metadata) releaseMar 21, 2018-
Map releaseMar 21, 2018-
UpdateOct 23, 2024-
Current statusOct 23, 2024Processing site: PDBj / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.025
  • Imaged by UCSF Chimera
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  • Surface view colored by radius
  • Surface level: 0.025
  • Imaged by UCSF Chimera
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  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-5ywo
  • Imaged by Jmol
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_6854.png

Downloads & links

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Map

FileDownload / File: emd_6854.map.gz / Format: CCP4 / Size: 1.4 GB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.38 Å/pix.
x 720 pix.
= 993.6 Å		1.38 Å/pix.
x 720 pix.
= 993.6 Å		1.38 Å/pix.
x 720 pix.
= 993.6 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.38 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.025 / Movie #1: 0.025
Minimum - Maximum-0.02884323 - 0.074024945
Average (Standard dev.)0.00012161364 (±0.005516465)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions720720720
Spacing720720720
CellA=B=C: 993.6 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.381.381.38
M x/y/z720720720
origin x/y/z0.0000.0000.000
length x/y/z993.600993.600993.600
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ300300300
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS720720720
D min/max/mean-0.0290.0740.000

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Supplemental data

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Sample components

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Entire : Complex of JEV with 2F2 Fab

EntireName: Complex of JEV with 2F2 Fab
Components
  • Complex: Complex of JEV with 2F2 Fab
    • Protein or peptide: JEV E protein
    • Protein or peptide: JEV M protein
    • Protein or peptide: 2F2 light chain
    • Protein or peptide: 2F2 heavy chain

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Supramolecule #1: Complex of JEV with 2F2 Fab

SupramoleculeName: Complex of JEV with 2F2 Fab / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Japanese encephalitis virus / Strain: P3

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Macromolecule #1: JEV E protein

MacromoleculeName: JEV E protein / type: protein_or_peptide / ID: 1 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Japanese encephalitis virus
Molecular weightTheoretical: 53.508684 KDa
SequenceString: FNCLGMGNRD FIEGASGATW VDLVLEGDSC LTIMANDKPT LDVRMINIEA SQLAEVRSYC YHASVTDIST VARCPMTGEA HNEKRADSS YVCKQGFTDR GWGNGCGLFG KGSIDTCAKF SCTSKAIGRT IQPENIKYEV GIFVHGTTTS ENHGNYSAQV G ASQAAKFT ...String:
FNCLGMGNRD FIEGASGATW VDLVLEGDSC LTIMANDKPT LDVRMINIEA SQLAEVRSYC YHASVTDIST VARCPMTGEA HNEKRADSS YVCKQGFTDR GWGNGCGLFG KGSIDTCAKF SCTSKAIGRT IQPENIKYEV GIFVHGTTTS ENHGNYSAQV G ASQAAKFT VTPNAPSITL KLGDYGEVTL DCEPRSGLNT EAFYVMTVGS KSFLVHREWF HDLALPWTPP SSTAWRNREL LM EFEEAHA TKQSVVALGS QEGGLHQALA GAIVVEYSSS VKLTSGHLKC RLKMDKLALK GTTYGMCTGK FSFAKNPADT GHG TVVIEL SYSGSDGPCK IPIVSVASLN DMTPVGRLVT VNPFVATSSA NSKVLVEMEP PFGDSYIVVG RGDKQINHHW HKAG STLGK AFLTTLKGAQ RLAALGDTAW DFGSIGGVFN SIGKAVHQVF GGAFRTLFGG MSWITQGLMG ALLLWMGVNA RDRSI ALAF LATGGVLLFL ATNVHA

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Macromolecule #2: JEV M protein

MacromoleculeName: JEV M protein / type: protein_or_peptide / ID: 2 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Japanese encephalitis virus
Molecular weightTheoretical: 8.250488 KDa
SequenceString:
SVSVQTHGES SLVNKTETWL DSTKATRYLM KTENWIIRNP GYAFLAAVLG WMLGSNNGQR VVFTILLLLV APAY

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Macromolecule #3: 2F2 light chain

MacromoleculeName: 2F2 light chain / type: protein_or_peptide / ID: 3 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 23.840303 KDa
SequenceString: DIVLTQSPAS LAVSLGQRAT ISCRASQSVS TSYMHWYQQK PGQPPRLLIY LVSNLESGVP SRFSGSGSGT DFTLNIHPVE AEDEATYYC QHIRELTRSE AGPSWLEIKR ADAAPTVSIF PPSSEQLTSG GASVVCFLNN FYPKDINVKW KIDGSERQNG V LNSWTDQD ...String:
DIVLTQSPAS LAVSLGQRAT ISCRASQSVS TSYMHWYQQK PGQPPRLLIY LVSNLESGVP SRFSGSGSGT DFTLNIHPVE AEDEATYYC QHIRELTRSE AGPSWLEIKR ADAAPTVSIF PPSSEQLTSG GASVVCFLNN FYPKDINVKW KIDGSERQNG V LNSWTDQD SKDSTYSMSS TLTLTKDEYE RHNSYTCEAT HKTSTSPIVK SFNRNEC

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Macromolecule #4: 2F2 heavy chain

MacromoleculeName: 2F2 heavy chain / type: protein_or_peptide / ID: 4 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 23.567473 KDa
SequenceString: QVQLMESGPE LKKPGETVKI SCTTSGYTFT DYAMHWVKQA PGKGLEWMGW INTATGEPTY AYDFKERFGF SLETSASTAF LQISNLKIE DTATYFCASD GRYWYFGVWG AGTSVTVSSP KTTPPSVYPL APVCGDTTGS MVTLGCLVKG YFPEPVTVTW N SGSLSSGV ...String:
QVQLMESGPE LKKPGETVKI SCTTSGYTFT DYAMHWVKQA PGKGLEWMGW INTATGEPTY AYDFKERFGF SLETSASTAF LQISNLKIE DTATYFCASD GRYWYFGVWG AGTSVTVSSP KTTPPSVYPL APVCGDTTGS MVTLGCLVKG YFPEPVTVTW N SGSLSSGV HTFPAVLQSD LYTLSSSVTV PSSTWPSETV TCNVAHPASS TKVDKKIVPR

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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

Concentration1 mg/mL
BufferpH: 7.4 / Details: PBS
GridModel: C-flat / Material: COPPER / Mesh: 400 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 30 sec.
VitrificationCryogen name: ETHANE / Chamber humidity: 95 % / Chamber temperature: 298 K / Instrument: FEI VITROBOT MARK III / Details: blot for 3 seconds before plunging.

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: FEI FALCON III (4k x 4k) / Detector mode: OTHER / Digitization - Dimensions - Width: 4000 pixel / Digitization - Dimensions - Height: 4000 pixel / Number grids imaged: 5 / Number real images: 1000 / Average exposure time: 8.0 sec. / Average electron dose: 25.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 100.0 µm / Calibrated defocus max: 3.0 µm / Calibrated defocus min: 1.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 3.0 µm / Nominal defocus min: 1.0 µm
Sample stageSpecimen holder model: OTHER
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 14203
Startup modelType of model: EMDB MAP
Final reconstructionApplied symmetry - Point group: I (icosahedral) / Resolution.type: BY AUTHOR / Resolution: 4.7 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 1.4) / Number images used: 14203
Initial angle assignmentType: RANDOM ASSIGNMENT
Final angle assignmentType: PROJECTION MATCHING / Software - Name: RELION (ver. 1.4)
Final 3D classificationNumber classes: 50 / Avg.num./class: 284 / Software - Name: RELION

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: FLEXIBLE FIT / Target criteria: correlation coefficient
Output model

PDB-5ywo:
Structure of JEV-2F2 Fab complex

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