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- EMDB-22818: Cryo-EM structure of Zika virus in complex with E protein cross-l... -

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Basic information

Entry
Database: EMDB / ID: EMD-22818
TitleCryo-EM structure of Zika virus in complex with E protein cross-linking human monoclonal antibody ADI30056
Map dataZIKV in complex with human monoclonal antibody ADI30056
Sample
  • Complex: Zika virus in complex with monoclonal antibody ADI30056
    • Complex: monoclonal antibody ADI30056
      • Protein or peptide: ADI30056 Fab heavy chain variable region
      • Protein or peptide: ADI30056 Fab light chain variable region
    • Virus: Zika virus ZIKV/H. sapiens/FrenchPolynesia/10087PF/2013
      • Protein or peptide: envelope protein E
      • Protein or peptide: membrane protein M
KeywordsZika Virus / Flavivirus / Zika-Antibody / VIRUS-IMMUNE SYSTEM complex
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 / negative regulation of innate immune response / ribonucleoside triphosphate phosphatase activity / viral capsid / double-stranded RNA binding / nucleoside-triphosphate phosphatase ...: / 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 / negative regulation of innate immune response / ribonucleoside triphosphate phosphatase activity / viral capsid / double-stranded RNA binding / nucleoside-triphosphate phosphatase / 4 iron, 4 sulfur cluster binding / mRNA (guanine-N7)-methyltransferase / methyltransferase cap1 / molecular adaptor activity / clathrin-dependent endocytosis of virus by host cell / methyltransferase cap1 activity / mRNA 5'-cap (guanine-N7-)-methyltransferase activity / RNA helicase activity / protein dimerization activity / host cell perinuclear region of cytoplasm / host cell endoplasmic reticulum membrane / RNA helicase / symbiont-mediated suppression of host innate immune response / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / symbiont entry into host cell / symbiont-mediated activation of host autophagy / RNA-directed RNA polymerase / serine-type endopeptidase activity / viral RNA genome replication / RNA-directed RNA polymerase activity / fusion of virus membrane with host endosome membrane / lipid binding / viral envelope / centrosome / GTP binding / virion attachment to host cell / host cell nucleus / virion membrane / structural molecule activity / ATP hydrolysis activity / proteolysis / extracellular region / ATP binding / metal ion binding / membrane
Similarity search - Function
Flavivirus non-structural protein NS2B / Flavivirus capsid protein C superfamily / Genome polyprotein, Flavivirus / : / Flavivirus non-structural protein NS4A / Flavivirus non-structural protein NS2B / Flavivirus non-structural protein NS4B / mRNA cap 0/1 methyltransferase / Flavivirus non-structural protein NS4B / Flavivirus non-structural protein NS4A ...Flavivirus non-structural protein NS2B / Flavivirus capsid protein C superfamily / Genome polyprotein, Flavivirus / : / Flavivirus non-structural protein NS4A / Flavivirus non-structural protein NS2B / Flavivirus non-structural protein NS4B / mRNA cap 0/1 methyltransferase / 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. / RNA-directed RNA polymerase, thumb domain, Flavivirus / Flavivirus RNA-directed RNA polymerase, thumb domain / RNA-directed RNA polymerase, flavivirus / Flavivirus RNA-directed RNA polymerase, fingers and palm domains / Flavivirus capsid protein C / Flavivirus capsid protein C / Flavivirus non-structural Protein NS1 / Flavivirus non-structural protein NS1 / Envelope glycoprotein M, flavivirus / Envelope glycoprotein M superfamily, flavivirus / Flavivirus envelope glycoprotein M / Flavivirus polyprotein propeptide / Flavivirus polyprotein propeptide superfamily / Flavivirus polyprotein propeptide / Flavivirus envelope glycoprotein E, stem/anchor domain / : / Flavivirus NS3 helicase, C-terminal helical domain / Flavivirus envelope glycoprotein E, Stem/Anchor domain / Flavivirus envelope glycoprotein E, Stem/Anchor domain superfamily / Flavivirus glycoprotein E, immunoglobulin-like domain / Flavivirus glycoprotein, immunoglobulin-like domain / Flavivirus glycoprotein central and dimerisation domain / Flavivirus glycoprotein, central and dimerisation domains / Flaviviral glycoprotein E, central domain, subdomain 1 / Flaviviral glycoprotein E, central domain, subdomain 2 / 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 speciesHomo sapiens (human) / Zika virus ZIKV/H. sapiens/FrenchPolynesia/10087PF/2013
Methodsingle particle reconstruction / cryo EM / Resolution: 4.0 Å
AuthorsSevvana M / Rogers TF
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)AI076331 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)AI073755 United States
CitationJournal: Viruses / Year: 2020
Title: Structural Basis of Zika Virus Specific Neutralization in Subsequent Flavivirus Infections.
Authors: Madhumati Sevvana / Thomas F Rogers / Andrew S Miller / Feng Long / Thomas Klose / Nathan Beutler / Yen-Chung Lai / Mara Parren / Laura M Walker / Geeta Buda / Dennis R Burton / Michael G ...Authors: Madhumati Sevvana / Thomas F Rogers / Andrew S Miller / Feng Long / Thomas Klose / Nathan Beutler / Yen-Chung Lai / Mara Parren / Laura M Walker / Geeta Buda / Dennis R Burton / Michael G Rossmann / Richard J Kuhn /
Abstract: Zika virus (ZIKV), a mosquito-borne human flavivirus that causes microcephaly and other neurological disorders, has been a recent focus for the development of flavivirus vaccines and therapeutics. We ...Zika virus (ZIKV), a mosquito-borne human flavivirus that causes microcephaly and other neurological disorders, has been a recent focus for the development of flavivirus vaccines and therapeutics. We report here a 4.0 Å resolution structure of the mature ZIKV in complex with ADI-30056, a ZIKV-specific human monoclonal antibody (hMAb) isolated from a ZIKV infected donor with a prior dengue virus infection. The structure shows that the hMAb interactions span across the E protein dimers on the virus surface, inhibiting conformational changes required for the formation of infectious fusogenic trimers similar to the hMAb, ZIKV-117. Structure-based functional analysis, and structure and sequence comparisons, identified ZIKV residues essential for neutralization and crucial for the evolution of highly potent E protein crosslinking Abs in ZIKV. Thus, this epitope, ZIKV's "Achilles heel", defined by the contacts between ZIKV and ADI-30056, could be a suitable target for the design of therapeutic antibodies.
History
DepositionOct 7, 2020-
Header (metadata) releaseDec 16, 2020-
Map releaseDec 16, 2020-
UpdateNov 13, 2024-
Current statusNov 13, 2024Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 3.5
  • Imaged by UCSF Chimera
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  • Surface view colored by radius
  • Surface level: 3.5
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7kcr
  • Surface level: 5
  • Imaged by UCSF Chimera
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  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-7kcr
  • Imaged by Jmol
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_22818.png

Downloads & links

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Map

FileDownload / File: emd_22818.map.gz / Format: CCP4 / Size: 4 GB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationZIKV in complex with human monoclonal antibody ADI30056
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.86 Å/pix.
x 1024 pix.
= 880.64 Å		0.86 Å/pix.
x 1024 pix.
= 880.64 Å		0.86 Å/pix.
x 1024 pix.
= 880.64 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.86 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 3.5 / Movie #1: 3.5
Minimum - Maximum-27.566092000000001 - 36.523342
Average (Standard dev.)0.016995663 (±1.2479379)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions102410241024
Spacing102410241024
CellA=B=C: 880.64 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.860.860.86
M x/y/z102410241024
origin x/y/z0.0000.0000.000
length x/y/z880.640880.640880.640
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS102410241024
D min/max/mean-27.56636.5230.017

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Supplemental data

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Half map: ZIKV in complex with human monoclonal antibody ADI30056 - Half Map 1

Fileemd_22818_half_map_1.map
AnnotationZIKV in complex with human monoclonal antibody ADI30056 - Half Map 1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: ZIKV in complex with human monoclonal antibody ADI30056 - Half Map 2

Fileemd_22818_half_map_2.map
AnnotationZIKV in complex with human monoclonal antibody ADI30056 - Half Map 2
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Zika virus in complex with monoclonal antibody ADI30056

EntireName: Zika virus in complex with monoclonal antibody ADI30056
Components
  • Complex: Zika virus in complex with monoclonal antibody ADI30056
    • Complex: monoclonal antibody ADI30056
      • Protein or peptide: ADI30056 Fab heavy chain variable region
      • Protein or peptide: ADI30056 Fab light chain variable region
    • Virus: Zika virus ZIKV/H. sapiens/FrenchPolynesia/10087PF/2013
      • Protein or peptide: envelope protein E
      • Protein or peptide: membrane protein M

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Supramolecule #1: Zika virus in complex with monoclonal antibody ADI30056

SupramoleculeName: Zika virus in complex with monoclonal antibody ADI30056
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Molecular weightTheoretical: 15 MDa

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Supramolecule #3: monoclonal antibody ADI30056

SupramoleculeName: monoclonal antibody ADI30056 / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #2: Zika virus ZIKV/H. sapiens/FrenchPolynesia/10087PF/2013

SupramoleculeName: Zika virus ZIKV/H. sapiens/FrenchPolynesia/10087PF/2013
type: virus / ID: 2 / Parent: 1 / Macromolecule list: #3-#4 / NCBI-ID: 2043570
Sci species name: Zika virus ZIKV/H. sapiens/FrenchPolynesia/10087PF/2013
Virus type: VIRION / Virus isolate: STRAIN / Virus enveloped: Yes / Virus empty: No
Host (natural)Organism: Homo sapiens (human)
Virus shellShell ID: 1 / Name: Envelope protein shell / Diameter: 500.0 Å / T number (triangulation number): 3

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Macromolecule #1: ADI30056 Fab heavy chain variable region

MacromoleculeName: ADI30056 Fab heavy chain variable region / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 13.467001 KDa
Recombinant expressionOrganism: Scheffersomyces stipitis (fungus)
SequenceString:
EVQLLESGGG VVQPGGSLRL SCTASGFTFR NFGIHWVRQA PGKRLEWVAF IRYDGRNKYY ADSVKGRFIS SRDNSKNMVY LDMKSLRPE DTAIYHCAAD GEETSPGSFD YWGQGTLVTV SS

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Macromolecule #2: ADI30056 Fab light chain variable region

MacromoleculeName: ADI30056 Fab light chain variable region / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 11.385728 KDa
Recombinant expressionOrganism: Scheffersomyces stipitis (fungus)
SequenceString:
DIVMTQTPSS LAASVGDSVT ITCRASESVS TVLNWYQHKP GKAPKLLIYA ASTLPSGVPS RFSGSGSGTD FTLSISSLQP EDFAIYYCQ QSYFSPRTFG GGTKVEIK

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Macromolecule #3: envelope protein E

MacromoleculeName: envelope protein E / type: protein_or_peptide / ID: 3 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Zika virus ZIKV/H. sapiens/FrenchPolynesia/10087PF/2013
Molecular weightTheoretical: 54.186762 KDa
Recombinant expressionOrganism: Zika virus ZIKV/H. sapiens/FrenchPolynesia/10087PF/2013
SequenceString: IRCIGVSNRD FVEGMSGGTW VDVVLEHGGC VTVMAQDKPT VDIELVTTTV SNMAEVRSYC YEASISDMAS DSRCPTQGEA YLDKQSDTQ YVCKRTLVDR GWGNGCGLFG KGSLVTCAKF ACSKKMTGKS IQPENLEYRI MLSVHGSQHS GMIVNDTGHE T DENRAKVE ...String:
IRCIGVSNRD FVEGMSGGTW VDVVLEHGGC VTVMAQDKPT VDIELVTTTV SNMAEVRSYC YEASISDMAS DSRCPTQGEA YLDKQSDTQ YVCKRTLVDR GWGNGCGLFG KGSLVTCAKF ACSKKMTGKS IQPENLEYRI MLSVHGSQHS GMIVNDTGHE T DENRAKVE ITPNSPRAEA TLGGFGSLGL DCEPRTGLDF SDLYYLTMNN KHWLVHKEWF HDIPLPWHAG ADTGTPHWNN KE ALVEFKD AHAKRQTVVV LGSQEGAVHT ALAGALEAEM DGAKGRLSSG HLKCRLKMDK LRLKGVSYSL CTAAFTFTKI PAE TLHGTV TVEVQYAGTD GPCKVPAQMA VDMQTLTPVG RLITANPVIT ESTENSKMML ELDPPFGDSY IVIGVGEKKI THHW HRSGS TIGKAFEATV RGAKRMAVLG DTAWDFGSVG GALNSLGKGI HQIFGAAFKS LFGGMSWFSQ ILIGTLLMWL GLNTK NGSI SLMCLALGGV LIFLSTA

UniProtKB: Genome polyprotein

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Macromolecule #4: membrane protein M

MacromoleculeName: membrane protein M / type: protein_or_peptide / ID: 4 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Zika virus ZIKV/H. sapiens/FrenchPolynesia/10087PF/2013
Molecular weightTheoretical: 8.496883 KDa
Recombinant expressionOrganism: Zika virus ZIKV/H. sapiens/FrenchPolynesia/10087PF/2013
SequenceString:
AVTLPSHSTR KLQTRSQTWL ESREYTKHLI RVENWIFRNP GFALAAAAIA WLLGSSTSQK VIYLVMILLI APAYS

UniProtKB: Genome polyprotein

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation state2D array

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Sample preparation

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 30.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 100.0 µm / Illumination mode: OTHER / Imaging mode: BRIGHT FIELD
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: 165789
Startup modelType of model: INSILICO MODEL
Final reconstructionApplied symmetry - Point group: I (icosahedral) / Algorithm: FOURIER SPACE / Resolution.type: BY AUTHOR / Resolution: 4.0 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: jspr / Number images used: 22330
Initial angle assignmentType: RANDOM ASSIGNMENT / Software - Name: jspr
Final angle assignmentType: PROJECTION MATCHING / Software - Name: jspr

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Atomic model buiding 1

Initial modelPDB ID:

6co8


Chain - Source name: PDB / Chain - Initial model type: experimental model
RefinementSpace: REAL / Protocol: FLEXIBLE FIT
Output model

PDB-7kcr:
Cryo-EM structure of Zika virus in complex with E protein cross-linking human monoclonal antibody ADI30056

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