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- EMDB-30883: Cryo-EM structure of Dengue virus serotype 1 strain WestPac 74 in... -

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Basic information

Entry
Database: EMDB / ID: EMD-30883
TitleCryo-EM structure of Dengue virus serotype 1 strain WestPac 74 in complex with human antibody 1C19 Fab at 37 deg C (Class 1 particle)
Map dataCryoEM map of DENV1 strain WestPac 74 in complex with Fab 1C19 at 37 deg C (Class 1)
Sample
  • Complex: Dengue virus serotype 1 strain WestPac 74 in complex with human antibody 1C19 Fab
    • Complex: Dengue virus 1
      • Protein or peptide: envelope proteinViral envelope
    • Complex: antibody 1C19 Fab
      • Protein or peptide: Anti-dengue virus human monoclonal antibody 1C19 Fab heavy chain
      • Protein or peptide: Anti-dengue virus human monoclonal antibody 1C19 Fab light chain
Keywordsdengue virus / human antibody / dengue-Fab structure / VIRUS / VIRUS-IMMUNE SYSTEM complex
Function / homology
Function and homology information


symbiont-mediated suppression of host JAK-STAT cascade via inhibition of host TYK2 activity / flavivirin / host cell mitochondrion / symbiont-mediated suppression of host JAK-STAT cascade via inhibition of STAT2 activity / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of MAVS activity / : / viral capsid / nucleoside-triphosphate phosphatase / double-stranded RNA binding / protein complex oligomerization ...symbiont-mediated suppression of host JAK-STAT cascade via inhibition of host TYK2 activity / flavivirin / host cell mitochondrion / symbiont-mediated suppression of host JAK-STAT cascade via inhibition of STAT2 activity / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of MAVS activity / : / viral capsid / nucleoside-triphosphate phosphatase / double-stranded RNA binding / protein complex oligomerization / monoatomic ion channel activity / 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 / RNA helicase activity / host cell endoplasmic reticulum membrane / host cell perinuclear region of cytoplasm / protein dimerization activity / RNA helicase / induction by virus of host autophagy / RNA-directed RNA polymerase / 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 / virion membrane / ATP hydrolysis activity / proteolysis / extracellular region / ATP binding / membrane / metal ion binding
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 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 / 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, chymotrypsin-like fold / DNA/RNA polymerase superfamily / Peptidase S1, PA clan / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Biological speciesDengue virus 1 / Homo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 19.0 Å
AuthorsFibriansah G / Ng TS
Funding support Singapore, United States, 3 items
OrganizationGrant numberCountry
National Research Foundation (NRF, Singapore)NRF-NRFI2016-01 Singapore
National Research Foundation (NRF, Singapore)NRF2017NRF-CRP001-027 Singapore
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)U54 AI 057157 United States
CitationJournal: PLoS Pathog / Year: 2021
Title: Antibody affinity versus dengue morphology influences neutralization.
Authors: Guntur Fibriansah / Elisa X Y Lim / Jan K Marzinek / Thiam-Seng Ng / Joanne L Tan / Roland G Huber / Xin-Ni Lim / Valerie S Y Chew / Victor A Kostyuchenko / Jian Shi / Ganesh S Anand / Peter ...Authors: Guntur Fibriansah / Elisa X Y Lim / Jan K Marzinek / Thiam-Seng Ng / Joanne L Tan / Roland G Huber / Xin-Ni Lim / Valerie S Y Chew / Victor A Kostyuchenko / Jian Shi / Ganesh S Anand / Peter J Bond / James E Crowe / Shee-Mei Lok /
Abstract: Different strains within a dengue serotype (DENV1-4) can have smooth, or "bumpy" surface morphologies with different antigenic characteristics at average body temperature (37°C). We determined the ...Different strains within a dengue serotype (DENV1-4) can have smooth, or "bumpy" surface morphologies with different antigenic characteristics at average body temperature (37°C). We determined the neutralizing properties of a serotype cross-reactive human monoclonal antibody (HMAb) 1C19 for strains with differing morphologies within the DENV1 and DENV2 serotypes. We mapped the 1C19 epitope to E protein domain II by hydrogen deuterium exchange mass spectrometry, cryoEM and molecular dynamics simulations, revealing that this epitope is likely partially hidden on the virus surface. We showed the antibody has high affinity for binding to recombinant DENV1 E proteins compared to those of DENV2, consistent with its strong neutralizing activities for all DENV1 strains tested regardless of their morphologies. This finding suggests that the antibody could out-compete E-to-E interaction for binding to its epitope. In contrast, for DENV2, HMAb 1C19 can only neutralize when the epitope becomes exposed on the bumpy-surfaced particle. Although HMAb 1C19 is not a suitable therapeutic candidate, this study with HMAb 1C19 shows the importance of choosing a high-affinity antibody that could neutralize diverse dengue virus morphologies for therapeutic purposes.
History
DepositionJan 18, 2021-
Header (metadata) releaseFeb 17, 2021-
Map releaseFeb 17, 2021-
UpdateMar 27, 2024-
Current statusMar 27, 2024Processing site: PDBj / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 2
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  • Surface view colored by radius
  • Surface level: 2
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  • Surface view with fitted model
  • Atomic models: PDB-7dwt
  • Surface level: 2
  • Imaged by UCSF Chimera
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  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-7dwt
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_30883.png

Downloads & links

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Map

FileDownload / File: emd_30883.map.gz / Format: CCP4 / Size: 512 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCryoEM map of DENV1 strain WestPac 74 in complex with Fab 1C19 at 37 deg C (Class 1)
Voxel sizeX=Y=Z: 1.71 Å
Density
Contour LevelBy AUTHOR: 2.0 / Movie #1: 2
Minimum - Maximum-5.6045275 - 9.710430000000001
Average (Standard dev.)0.031006996 (±0.99434733)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin-256-256-256
Dimensions512512512
Spacing512512512
CellA=B=C: 875.52 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.711.711.71
M x/y/z512512512
origin x/y/z0.0000.0000.000
length x/y/z875.520875.520875.520
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ120120120
MAP C/R/S123
start NC/NR/NS-256-256-256
NC/NR/NS512512512
D min/max/mean-5.6059.7100.031

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Supplemental data

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Sample components

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Entire : Dengue virus serotype 1 strain WestPac 74 in complex with human a...

EntireName: Dengue virus serotype 1 strain WestPac 74 in complex with human antibody 1C19 Fab
Components
  • Complex: Dengue virus serotype 1 strain WestPac 74 in complex with human antibody 1C19 Fab
    • Complex: Dengue virus 1
      • Protein or peptide: envelope proteinViral envelope
    • Complex: antibody 1C19 Fab
      • Protein or peptide: Anti-dengue virus human monoclonal antibody 1C19 Fab heavy chain
      • Protein or peptide: Anti-dengue virus human monoclonal antibody 1C19 Fab light chain

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Supramolecule #1: Dengue virus serotype 1 strain WestPac 74 in complex with human a...

SupramoleculeName: Dengue virus serotype 1 strain WestPac 74 in complex with human antibody 1C19 Fab
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Details: Dengue virus serotype 1 strain WestPac 74 was grown in Aedes albopictus C6/36 cells.
Source (natural)Organism: Dengue virus 1 / Strain: Western Pacific 74

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Supramolecule #2: Dengue virus 1

SupramoleculeName: Dengue virus 1 / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1 / Details: Dengue virus serotype 1 strain WestPac 74
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #3: antibody 1C19 Fab

SupramoleculeName: antibody 1C19 Fab / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #2-#3 / Details: antibody 1C19 Fab

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Macromolecule #1: envelope protein

MacromoleculeName: envelope protein / type: protein_or_peptide / ID: 1 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Dengue virus 1 / Strain: WestPac 74
Molecular weightTheoretical: 53.910871 KDa
SequenceString: MRCVGIGNRD FVEGLSGATW VDVVLEHGSC VTTMAKDKPT LDIELLKTEV TNPAVLRKLC IEAKISNTTT DSRCPTQGEA TLVEEQDTN FVCRRTFVDR GWGNGCGLFG KGSLITCAKF KCVTKLEGKI VQYENLKYSV IVTVHTGDQH QVGNETTEHG T IATITPQA ...String:
MRCVGIGNRD FVEGLSGATW VDVVLEHGSC VTTMAKDKPT LDIELLKTEV TNPAVLRKLC IEAKISNTTT DSRCPTQGEA TLVEEQDTN FVCRRTFVDR GWGNGCGLFG KGSLITCAKF KCVTKLEGKI VQYENLKYSV IVTVHTGDQH QVGNETTEHG T IATITPQA PTSEIQLTDY GALTLDCSPR TGLDFNEMVL LTMEKKSWLV HKQWFLDLPL PWTSGASTSQ ETWNRQDLLV TF KTAHAKK QEVVVLGSQE GAMHTALTGA TEIQTSGTTT IFAGHLKCRL KMDKLTLKGM SYVMCTGSFK LEKEVAETQH GTV LVQVKY EGTDAPCKIP FSSQDEKGVT QNGRLITANP IVTDKEKPVN IEAEPPFGES YIVVGAGEKA LKLSWFKKGS SIGK MFEAT ARGARRMAIL GDTAWDFGSI GGVFTSVGKL IHQIFGTAYG VLFSGVSWTM KIGIGILLTW LGLNSRSTSL SMTCI AVGM VTLYLGVMVQ A

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Macromolecule #2: Anti-dengue virus human monoclonal antibody 1C19 Fab heavy chain

MacromoleculeName: Anti-dengue virus human monoclonal antibody 1C19 Fab heavy chain
type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 13.167631 KDa
SequenceString:
QVQLVESGGG VVQPGRSLRL SCAASGFIFS NYGMHWVRQA PGKGLEWVAV ISYDGSDKRY ADSVRGRFTI SRDNSKNTLF LQVTSLRAE DTAVYYCAKE LSGYDPGFEY WGQGTPVTVS S

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Macromolecule #3: Anti-dengue virus human monoclonal antibody 1C19 Fab light chain

MacromoleculeName: Anti-dengue virus human monoclonal antibody 1C19 Fab light chain
type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 11.584849 KDa
SequenceString:
DIQMTQSPST LSASVGDRVT ITCRASQSIN TWLAWYQQKP GKAPKLLIYK ASSLESGVPS RFSGSGSGTE FTLTISSLQP DDFATYYCQ QYESYATFGQ GTKVDIK

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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: NTE buffer (12 mM Tris-HCl pH 8.0, 120 mM NaCl and 1 mM EDTA)
VitrificationCryogen name: ETHANE
DetailsThe purified virus was incubated with Fab 1C19 at 37 deg C for 30 min with a molar ratio of one Fab for every E-protein and followed by incubation at 4 deg C for 2 h.

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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
Image recordingFilm or detector model: FEI FALCON II (4k x 4k) / Average electron dose: 18.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 4301
Startup modelType of model: EMDB MAP
EMDB ID:

2142

Initial angle assignmentType: COMMON LINE / Software - Name: MPSA
Final angle assignmentType: COMMON LINE / Software - Name: MPSA
Final reconstructionApplied symmetry - Point group: I (icosahedral) / Resolution.type: BY AUTHOR / Resolution: 19.0 Å / Resolution method: FSC 0.5 CUT-OFF / Software - Name: MPSA / Number images used: 1116

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Atomic model buiding 1

Initial model
PDB IDChain

4cct

source_name: PDB, initial_model_type: experimental model

4hie

source_name: PDB, initial_model_type: experimental model

4kq3

source_name: PDB, initial_model_type: experimental model
RefinementProtocol: RIGID BODY FIT
Output model

PDB-7dwt:
Cryo-EM structure of Dengue virus serotype 1 strain WestPac 74 in complex with human antibody 1C19 Fab at 37 deg C (Class 1 particle)

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