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- EMDB-2967: Cryo-EM structure of Dengue virus serotype 2 in complex with anti... -

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Basic information

Entry
Database: EMDB / ID: EMD-2967
TitleCryo-EM structure of Dengue virus serotype 2 in complex with antigen-binding fragments of human antibody 2D22
Map dataReconstruction of Dengue virus 2 strain PVP94/07 (a clinical isolate) in complex with human antibody 2D22 Fab
Sample
  • Sample: Dengue virus serotype 2 strain PVP94/07 (a clinical isolate) complexed with Fab fragments of human antibody 2D22.
  • Virus: Dengue Virus serotype 2
  • Protein or peptide: Antigen-binding fragment of human antibody 2D22
Keywordsdengue virus / human antibody / cryo-EM / neutralization
Function / homology
Function and homology information


symbiont-mediated suppression of host JAK-STAT cascade via inhibition of host TYK2 activity / flavivirin / symbiont-mediated suppression of host JAK-STAT cascade via inhibition of STAT2 activity / ribonucleoside triphosphate phosphatase activity / viral capsid / nucleoside-triphosphate phosphatase / double-stranded RNA binding / clathrin-dependent endocytosis of virus by host cell / mRNA (nucleoside-2'-O-)-methyltransferase activity / mRNA 5'-cap (guanine-N7-)-methyltransferase activity ...symbiont-mediated suppression of host JAK-STAT cascade via inhibition of host TYK2 activity / flavivirin / symbiont-mediated suppression of host JAK-STAT cascade via inhibition of STAT2 activity / ribonucleoside triphosphate phosphatase activity / viral capsid / nucleoside-triphosphate phosphatase / double-stranded RNA binding / clathrin-dependent endocytosis of virus by host cell / mRNA (nucleoside-2'-O-)-methyltransferase activity / mRNA 5'-cap (guanine-N7-)-methyltransferase activity / RNA helicase activity / membrane => GO:0016020 / host cell endoplasmic reticulum membrane / protein dimerization activity / RNA helicase / induction by virus of host autophagy / viral RNA genome replication / RNA-dependent RNA polymerase activity / serine-type endopeptidase activity / fusion of virus membrane with host endosome membrane / viral envelope / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / host cell nucleus / structural molecule activity / virion attachment to host cell / endoplasmic reticulum membrane / virion membrane / proteolysis / extracellular region / ATP binding / membrane / metal ion binding / nucleus
Similarity search - Function
: / Flavivirus envelope glycoprotein E, stem/anchor domain / RNA-directed RNA polymerase, thumb domain, Flavivirus / Flavivirus RNA-directed RNA polymerase, thumb domain / Flavivirus capsid protein C superfamily / Flavivirus non-structural protein NS2B / Flavivirus NS3 helicase, C-terminal helical domain / Genome polyprotein, Flavivirus / Flavivirus non-structural protein NS4A / Flavivirus non-structural protein NS2B ...: / Flavivirus envelope glycoprotein E, stem/anchor domain / RNA-directed RNA polymerase, thumb domain, Flavivirus / Flavivirus RNA-directed RNA polymerase, thumb domain / Flavivirus capsid protein C superfamily / Flavivirus non-structural protein NS2B / Flavivirus NS3 helicase, C-terminal helical domain / Genome polyprotein, Flavivirus / Flavivirus non-structural protein NS4A / Flavivirus non-structural protein NS2B / Flavivirus capsid protein C / Flavivirus non-structural protein NS4B / mRNA cap 0/1 methyltransferase / Flavivirus capsid protein C / Flavivirus non-structural protein NS4B / Flavivirus non-structural protein NS4A / Flavivirus NS2B domain profile. / mRNA cap 0 and cap 1 methyltransferase (EC 2.1.1.56 and EC 2.1.1.57) domain profile. / Flavivirus non-structural protein NS2A / Flavivirus non-structural protein NS2A / Flavivirus NS3, petidase S7 / Peptidase S7, Flavivirus NS3 serine protease / Flavivirus NS3 protease (NS3pro) domain profile. / Envelope glycoprotein M, flavivirus / Flavivirus envelope glycoprotein M / 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 superfamily, flavivirus / Flavivirus polyprotein propeptide / Flavivirus polyprotein propeptide superfamily / Flavivirus polyprotein propeptide / Flaviviral glycoprotein E, central domain, subdomain 1 / Flaviviral glycoprotein E, central domain, subdomain 2 / Flavivirus envelope glycoprotein E, Stem/Anchor domain / Flavivirus glycoprotein E, immunoglobulin-like domain / Flavivirus envelope glycoprotein E, Stem/Anchor domain superfamily / Flavivirus glycoprotein, immunoglobulin-like domain / Flavivirus glycoprotein central and dimerisation 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 / Immunoglobulin V-Type / Immunoglobulin V-set domain / Immunoglobulin V-set 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 / Immunoglobulin subtype / Immunoglobulin / Immunoglobulin/major histocompatibility complex, conserved site / Immunoglobulins and major histocompatibility complex proteins signature. / Immunoglobulin C-Type / Immunoglobulin C1-set / Immunoglobulin C1-set domain / RNA-directed RNA polymerase, catalytic domain / RdRp of positive ssRNA viruses catalytic domain profile. / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like domain superfamily / S-adenosyl-L-methionine-dependent methyltransferase superfamily / Peptidase S1, PA clan, chymotrypsin-like fold / DNA/RNA polymerase superfamily / Peptidase S1, PA clan / Immunoglobulin-like fold / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Envelope protein E / Genome polyprotein / Core protein / IgG L chain
Similarity search - Component
Biological speciesHomo sapiens (human) / Dengue Virus serotype 2
Methodsingle particle reconstruction / cryo EM / Resolution: 6.5 Å
AuthorsFibriansah G / Ibarra KD / Ng TS / Smith SA / Tan JL / Lim XN / Ooi JSG / Kostyuchenko VA / Wang J / de Silva AM ...Fibriansah G / Ibarra KD / Ng TS / Smith SA / Tan JL / Lim XN / Ooi JSG / Kostyuchenko VA / Wang J / de Silva AM / Harris E / Crowe JE / Lok SM
CitationJournal: Science / Year: 2015
Title: DENGUE VIRUS. Cryo-EM structure of an antibody that neutralizes dengue virus type 2 by locking E protein dimers.
Authors: Guntur Fibriansah / Kristie D Ibarra / Thiam-Seng Ng / Scott A Smith / Joanne L Tan / Xin-Ni Lim / Justin S G Ooi / Victor A Kostyuchenko / Jiaqi Wang / Aravinda M de Silva / Eva Harris / ...Authors: Guntur Fibriansah / Kristie D Ibarra / Thiam-Seng Ng / Scott A Smith / Joanne L Tan / Xin-Ni Lim / Justin S G Ooi / Victor A Kostyuchenko / Jiaqi Wang / Aravinda M de Silva / Eva Harris / James E Crowe / Shee-Mei Lok /
Abstract: There are four closely-related dengue virus (DENV) serotypes. Infection with one serotype generates antibodies that may cross-react and enhance infection with other serotypes in a secondary infection. ...There are four closely-related dengue virus (DENV) serotypes. Infection with one serotype generates antibodies that may cross-react and enhance infection with other serotypes in a secondary infection. We demonstrated that DENV serotype 2 (DENV2)-specific human monoclonal antibody (HMAb) 2D22 is therapeutic in a mouse model of antibody-enhanced severe dengue disease. We determined the cryo-electron microscopy (cryo-EM) structures of HMAb 2D22 complexed with two different DENV2 strains. HMAb 2D22 binds across viral envelope (E) proteins in the dimeric structure, which probably blocks the E protein reorganization required for virus fusion. HMAb 2D22 "locks" two-thirds of or all dimers on the virus surface, depending on the strain, but neutralizes these DENV2 strains with equal potency. The epitope defined by HMAb 2D22 is a potential target for vaccines and therapeutics.
History
DepositionMar 29, 2015-
Header (metadata) releaseApr 15, 2015-
Map releaseJul 15, 2015-
UpdateJul 15, 2015-
Current statusJul 15, 2015Processing site: PDBe / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 3
  • Imaged by UCSF Chimera
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  • Surface view colored by radius
  • Surface level: 3
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-4uif
  • Surface level: 3
  • Imaged by UCSF Chimera
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  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-4uif
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Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_2967.png

Downloads & links

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Map

FileDownload / File: emd_2967.map.gz / Format: CCP4 / Size: 500 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationReconstruction of Dengue virus 2 strain PVP94/07 (a clinical isolate) in complex with human antibody 2D22 Fab
Voxel sizeX=Y=Z: 1.688 Å
Density
Contour LevelBy AUTHOR: 2.0 / Movie #1: 3
Minimum - Maximum-10.67656708 - 14.261778830000001
Average (Standard dev.)-0.05019815 (±0.96412933)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin-256-256-256
Dimensions512512512
Spacing512512512
CellA=B=C: 864.256 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.6881.6881.688
M x/y/z512512512
origin x/y/z0.0000.0000.000
length x/y/z864.256864.256864.256
α/β/γ90.00090.00090.000
start NX/NY/NZ-147-147-146
NX/NY/NZ294294294
MAP C/R/S123
start NC/NR/NS-256-256-256
NC/NR/NS512512512
D min/max/mean-10.67714.262-0.050

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Supplemental data

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Sample components

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Entire : Dengue virus serotype 2 strain PVP94/07 (a clinical isolate) comp...

EntireName: Dengue virus serotype 2 strain PVP94/07 (a clinical isolate) complexed with Fab fragments of human antibody 2D22.
Components
  • Sample: Dengue virus serotype 2 strain PVP94/07 (a clinical isolate) complexed with Fab fragments of human antibody 2D22.
  • Virus: Dengue Virus serotype 2
  • Protein or peptide: Antigen-binding fragment of human antibody 2D22

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Supramolecule #1000: Dengue virus serotype 2 strain PVP94/07 (a clinical isolate) comp...

SupramoleculeName: Dengue virus serotype 2 strain PVP94/07 (a clinical isolate) complexed with Fab fragments of human antibody 2D22.
type: sample / ID: 1000 / Number unique components: 2

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Supramolecule #1: Dengue Virus serotype 2

SupramoleculeName: Dengue Virus serotype 2 / type: virus / ID: 1 / Sci species name: Dengue Virus serotype 2 / Sci species strain: PVP94/07 / Virus type: VIRION / Virus isolate: STRAIN / Virus enveloped: Yes / Virus empty: No
Host (natural)Organism: Homo sapiens (human) / synonym: VERTEBRATES
Host systemOrganism: Aedes albopictus (Asian tiger mosquito) / Recombinant cell: C6/36

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Macromolecule #1: Antigen-binding fragment of human antibody 2D22

MacromoleculeName: Antigen-binding fragment of human antibody 2D22 / type: protein_or_peptide / ID: 1
Details: 180 copies of Fab 2D22 molecule bind to virus surface
Number of copies: 180 / Recombinant expression: No
Source (natural)Organism: Homo sapiens (human) / synonym: Human / Cell: memory B-cell
Molecular weightTheoretical: 50 KDa

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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

BufferpH: 8 / Details: 10 mM Tris-HCl pH 8.0, 120 mM NaCl and 1 mM EDTA
GridDetails: ultra-thin carbon-coated lacey carbon grid
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Instrument: FEI VITROBOT MARK IV
Method: blotted with filter paper for 2 seconds prior to snap freezing

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: SPOT SCAN / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm / Nominal defocus max: 0.0047 µm / Nominal defocus min: 0.0015 µm / Nominal magnification: 47000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
DateFeb 5, 2014
Image recordingCategory: CCD / Film or detector model: FEI FALCON II (4k x 4k) / Number real images: 94 / Average electron dose: 20 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionDetails: Each particle
Final reconstructionApplied symmetry - Point group: I (icosahedral) / Algorithm: OTHER / Resolution.type: BY AUTHOR / Resolution: 6.5 Å / Resolution method: OTHER / Software - Name: EMAN, EMAN2, MPSA / Number images used: 2485
DetailsThe particles were manually selected

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Atomic model buiding 1

Initial modelPDB ID:

3j27


Chain - #0 - Chain ID: A / Chain - #1 - Chain ID: B / Chain - #2 - Chain ID: C / Chain - #3 - Chain ID: D / Chain - #4 - Chain ID: E / Chain - #5 - Chain ID: F
SoftwareName: Chimera, NAMD/MDFF
DetailsInitially fitted in Chimera and refined using NAMD/MDFF
RefinementSpace: REAL / Protocol: FLEXIBLE FIT / Target criteria: real-space correlation
Output model

PDB-4uif:
Cryo-EM structure of Dengue virus serotype 2 in complex with antigen-binding fragments of human antibody 2D22

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