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- EMDB-9131: Cryo-EM structure of the ZIKV virion in complex with Fab fragment... -

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Basic information

Entry
Database: EMDB / ID: EMD-9131
TitleCryo-EM structure of the ZIKV virion in complex with Fab fragments of the potently neutralizing human monoclonal antibody ZIKV-195
Map dataZIKV virion in complex with Fab fragments of the potently neutralizing human monoclonal antibody ZIKV-195. Different contour levels are required to visualize the viral components and the bound Fab molecules.
Sample
  • Complex: ZIKV virion in complex with Fab fragments of the potently neutralizing human monoclonal antibody ZIKV-195
    • Complex: monoclonal antibody ZIKV-195
      • Protein or peptide: monoclonal antibody ZIKV-195 heavy chain
      • Protein or peptide: monoclonal antibody ZIKV-195 light chain
    • Virus: Zika virus (isolate ZIKV/Human/French Polynesia/10087PF/2013)
      • Protein or peptide: E protein
      • Protein or peptide: M protein
Function / homology
Function and homology information


symbiont-mediated suppression of host JAK-STAT cascade via inhibition of host TYK2 activity / immunoglobulin complex / flavivirin / 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 / viral capsid / nucleoside-triphosphate phosphatase / double-stranded RNA binding / 4 iron, 4 sulfur cluster binding ...symbiont-mediated suppression of host JAK-STAT cascade via inhibition of host TYK2 activity / immunoglobulin complex / flavivirin / 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 / viral capsid / nucleoside-triphosphate phosphatase / double-stranded RNA binding / 4 iron, 4 sulfur cluster binding / 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 / adaptive immune response / host cell endoplasmic reticulum membrane / host cell perinuclear region of cytoplasm / protein dimerization activity / molecular adaptor activity / RNA helicase / immune response / 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 / centrosome / viral envelope / lipid binding / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / host cell nucleus / virion attachment to host cell / GTP binding / virion membrane / structural molecule activity / ATP hydrolysis activity / proteolysis / extracellular space / extracellular region / ATP binding / membrane / metal ion binding / plasma membrane
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 / 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 / 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 / DNA/RNA polymerase superfamily / Immunoglobulin-like fold / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Genome polyprotein / Immunoglobulin lambda variable 1-36
Similarity search - Component
Biological speciesHomo sapiens (human) / ZIKV (virus) / Human (human) / Zika virus (isolate ZIKV/Human/French Polynesia/10087PF/2013)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.0 Å
AuthorsLong F / Rossmann MG
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Center for Research Resources (NIH/NCRR)AI076331 United States
CitationJournal: Proc Natl Acad Sci U S A / Year: 2019
Title: Structural basis of a potent human monoclonal antibody against Zika virus targeting a quaternary epitope.
Authors: Feng Long / Michael Doyle / Estefania Fernandez / Andrew S Miller / Thomas Klose / Madhumati Sevvana / Aubrey Bryan / Edgar Davidson / Benjamin J Doranz / Richard J Kuhn / Michael S Diamond ...Authors: Feng Long / Michael Doyle / Estefania Fernandez / Andrew S Miller / Thomas Klose / Madhumati Sevvana / Aubrey Bryan / Edgar Davidson / Benjamin J Doranz / Richard J Kuhn / Michael S Diamond / James E Crowe / Michael G Rossmann /
Abstract: Zika virus (ZIKV) is a major human pathogen and member of the genus in the Flaviviridae family. In contrast to most other insect-transmitted flaviviruses, ZIKV also can be transmitted sexually and ...Zika virus (ZIKV) is a major human pathogen and member of the genus in the Flaviviridae family. In contrast to most other insect-transmitted flaviviruses, ZIKV also can be transmitted sexually and from mother to fetus in humans. During recent outbreaks, ZIKV infections have been linked to microcephaly, congenital disease, and Guillain-Barré syndrome. Neutralizing antibodies have potential as therapeutic agents. We report here a 4-Å-resolution cryo-electron microscopy structure of the ZIKV virion in complex with Fab fragments of the potently neutralizing human monoclonal antibody ZIKV-195. The footprint of the ZIKV-195 Fab fragment expands across two adjacent envelope (E) protein protomers. ZIKV neutralization by this antibody is presumably accomplished by cross-linking the E proteins, which likely prevents formation of E protein trimers required for fusion of the viral and cellular membranes. A single dose of ZIKV-195 administered 5 days after virus inoculation showed marked protection against lethality in a stringent mouse model of infection.
History
DepositionSep 19, 2018-
Header (metadata) releaseOct 3, 2018-
Map releaseJan 16, 2019-
UpdateJul 29, 2020-
Current statusJul 29, 2020Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 15
  • Imaged by UCSF Chimera
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  • Surface view colored by radius
  • Surface level: 15
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6mid
  • Surface level: 15
  • Imaged by UCSF Chimera
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  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-6mid
  • Imaged by Jmol
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_9131.png

Downloads & links

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Map

FileDownload / File: emd_9131.map.gz / Format: CCP4 / Size: 512 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationZIKV virion in complex with Fab fragments of the potently neutralizing human monoclonal antibody ZIKV-195. Different contour levels are required to visualize the viral components and the bound Fab molecules.
Voxel sizeX=Y=Z: 1.62 Å
Density
Contour LevelBy AUTHOR: 15 / Movie #1: 15
Minimum - Maximum-101.69505 - 169.9646
Average (Standard dev.)0.16021295 (±7.2527075)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions512512512
Spacing512512512
CellA=B=C: 829.44 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.621.621.62
M x/y/z512512512
origin x/y/z0.0000.0000.000
length x/y/z829.440829.440829.440
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS512512512
D min/max/mean-101.695169.9650.160

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Supplemental data

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Half map: Half map #1

Fileemd_9131_half_map_1.map
AnnotationHalf map #1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map #2

Fileemd_9131_half_map_2.map
AnnotationHalf 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 : ZIKV virion in complex with Fab fragments of the potently neutral...

EntireName: ZIKV virion in complex with Fab fragments of the potently neutralizing human monoclonal antibody ZIKV-195
Components
  • Complex: ZIKV virion in complex with Fab fragments of the potently neutralizing human monoclonal antibody ZIKV-195
    • Complex: monoclonal antibody ZIKV-195
      • Protein or peptide: monoclonal antibody ZIKV-195 heavy chain
      • Protein or peptide: monoclonal antibody ZIKV-195 light chain
    • Virus: Zika virus (isolate ZIKV/Human/French Polynesia/10087PF/2013)
      • Protein or peptide: E protein
      • Protein or peptide: M protein

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Supramolecule #1: ZIKV virion in complex with Fab fragments of the potently neutral...

SupramoleculeName: ZIKV virion in complex with Fab fragments of the potently neutralizing human monoclonal antibody ZIKV-195
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Details: Purified from infected Vero cells overexpressing the furin protease

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Supramolecule #3: monoclonal antibody ZIKV-195

SupramoleculeName: monoclonal antibody ZIKV-195 / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #3-#4
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #2: Zika virus (isolate ZIKV/Human/French Polynesia/10087PF/2013)

SupramoleculeName: Zika virus (isolate ZIKV/Human/French Polynesia/10087PF/2013)
type: virus / ID: 2 / Parent: 1 / Macromolecule list: #1-#2 / NCBI-ID: 2043570
Sci species name: Zika virus (isolate ZIKV/Human/French Polynesia/10087PF/2013)
Sci species strain: isolate ZIKV/Human/French Polynesia/10087PF/2013
Virus type: VIRION / Virus isolate: STRAIN / Virus enveloped: Yes / Virus empty: No

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Macromolecule #1: E protein

MacromoleculeName: E protein / type: protein_or_peptide / ID: 1 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: ZIKV (virus) / Strain: isolate ZIKV/Human/French Polynesia/10087PF/2013
Molecular weightTheoretical: 54.444051 KDa
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 LIFLSTAVSA

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Macromolecule #2: M protein

MacromoleculeName: M protein / type: protein_or_peptide / ID: 2 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: ZIKV (virus) / Strain: isolate ZIKV/Human/French Polynesia/10087PF/2013
Molecular weightTheoretical: 8.496883 KDa
SequenceString:
AVTLPSHSTR KLQTRSQTWL ESREYTKHLI RVENWIFRNP GFALAAAAIA WLLGSSTSQK VIYLVMILLI APAYS

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Macromolecule #3: monoclonal antibody ZIKV-195 heavy chain

MacromoleculeName: monoclonal antibody ZIKV-195 heavy chain / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Human (human)
Molecular weightTheoretical: 14.148739 KDa
SequenceString:
QVQLVESGGG VVHPGRSLRL SCAASGFTFS SSAMHWVRQA PGKGLEWVAV ISYDGSNKYY GDSVKGRFTI SRDNSKNTLY LQMHSLRAE DTAVYYCAKD RDAYNTVGYF AYYYGMDVWG QGTLVTVSS

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Macromolecule #4: monoclonal antibody ZIKV-195 light chain

MacromoleculeName: monoclonal antibody ZIKV-195 light chain / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Human (human)
Molecular weightTheoretical: 11.750902 KDa
SequenceString:
QSVLTQPPSV SEAPRQRVTI SCSGSSSNIG NNAVNWYQQL PGKAPKLLIY YDDLLPSGVS DRFSGSKSGT SASLAISGLQ SEDEADYYC AAWDDSLTRY VFGTGTKVTV L

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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

Concentration1.00 mg/mL
BufferpH: 8
Component:
ConcentrationNameFormula
20.0 mMTris
120.0 mMsodium chlorideNaClSodium chloride
1.0 mMEDTAEthylenediaminetetraacetic acid

Details: NTE buffer at pH 8.0
GridDetails: unspecified
VitrificationCryogen name: ETHANE / Chamber humidity: 90 % / Chamber temperature: 298 K / Instrument: GATAN CRYOPLUNGE 3
DetailsFab fragments were mixed with purified mature virus particles to make complexes.

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Number real images: 1691 / Average electron dose: 30.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionSoftware - Name: CTFFIND (ver. 4)
Initial angle assignmentType: RANDOM ASSIGNMENT / Software - Name: jspr
Final 3D classificationSoftware - Name: RELION
Final angle assignmentType: PROJECTION MATCHING / Software - Name: jspr
Final reconstructionApplied symmetry - Point group: I (icosahedral) / Resolution.type: BY AUTHOR / Resolution: 4.0 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: jspr
Details: The map was masked by removing the internal nucleic acid region and the external background region.
Number images used: 10687
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

6co8

DetailsThe occupancy of bound Fabs was low. Due to poor density, only the variable domain of Fab molecule was modeled and fit into one of the three Fab binding sites on each icosahedral asymmetric unit.
RefinementSpace: REAL / Protocol: FLEXIBLE FIT
Output model

PDB-6mid:
Cryo-EM structure of the ZIKV virion in complex with Fab fragments of the potently neutralizing human monoclonal antibody ZIKV-195

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