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- EMDB-33718: ZIKV_Fab_G9E -

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Basic information

Entry
Database: EMDB / ID: EMD-33718
TitleZIKV_Fab_G9E
Map data
Sample
  • Complex: Zika virus ZIKV/H. sapiens/FrenchPolynesia/10087PF/2013
    • Complex: Zika virus ZIKV/H.
      • Protein or peptide: E protein
      • Protein or peptide: M protein
    • Complex: heavy chain, light chain
      • Protein or peptide: light chain
    • Protein or peptide: heavy chain
Keywordsvirus complexed with antibody / VIRUS
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 / symbiont-mediated suppression of host JAK-STAT cascade via inhibition of STAT1 activity / negative regulation of innate immune response / ribonucleoside triphosphate phosphatase activity / double-stranded RNA binding / viral capsid / nucleoside-triphosphate phosphatase / 4 iron, 4 sulfur cluster binding ...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 / symbiont-mediated suppression of host JAK-STAT cascade via inhibition of STAT1 activity / negative regulation of innate immune response / ribonucleoside triphosphate phosphatase activity / double-stranded RNA binding / viral capsid / nucleoside-triphosphate phosphatase / 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 / molecular adaptor activity / RNA helicase activity / host cell endoplasmic reticulum membrane / host cell perinuclear region of cytoplasm / protein dimerization activity / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / RNA helicase / symbiont entry into host cell / induction by virus of host autophagy / RNA-directed RNA polymerase / 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 / centrosome / viral envelope / lipid binding / host cell nucleus / virion attachment to host cell / GTP binding / 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 / RNA-directed RNA polymerase, thumb domain, Flavivirus / Flavivirus RNA-directed RNA polymerase, thumb domain / Flavivirus non-structural protein NS2B / Flavivirus envelope glycoprotein E, stem/anchor domain / : / Flavivirus NS3 helicase, C-terminal helical domain / Genome polyprotein, Flavivirus / Flavivirus non-structural protein NS4A ...: / Flavivirus capsid protein C superfamily / RNA-directed RNA polymerase, thumb domain, Flavivirus / Flavivirus RNA-directed RNA polymerase, thumb domain / Flavivirus non-structural protein NS2B / Flavivirus envelope glycoprotein E, stem/anchor domain / : / 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. / 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 / Flavivirus envelope glycoprotein M / 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 / DNA/RNA polymerase superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Genome polyprotein / Genome polyprotein
Similarity search - Component
Biological speciesZika virus ZIKV/H. sapiens/FrenchPolynesia/10087PF/2013 / Homo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 5.9 Å
AuthorsShu B / Thiam-Seng N / Lok S
Funding support Singapore, 3 items
OrganizationGrant numberCountry
National Research Foundation (NRF, Singapore)NRF2017NRF-CRP001-027 Singapore
National Research Foundation (NRF, Singapore)NRF-NRFI2016-01 Singapore
National Research Foundation (NRF, Singapore)NRF2016NRF-CRP001-063 Singapore
CitationJournal: PLoS Pathog / Year: 2023
Title: Structure and neutralization mechanism of a human antibody targeting a complex Epitope on Zika virus.
Authors: Cameron Adams / Derek L Carbaugh / Bo Shu / Thiam-Seng Ng / Izabella N Castillo / Ryan Bhowmik / Bruno Segovia-Chumbez / Ana C Puhl / Stephen Graham / Sean A Diehl / Helen M Lazear / Shee- ...Authors: Cameron Adams / Derek L Carbaugh / Bo Shu / Thiam-Seng Ng / Izabella N Castillo / Ryan Bhowmik / Bruno Segovia-Chumbez / Ana C Puhl / Stephen Graham / Sean A Diehl / Helen M Lazear / Shee-Mei Lok / Aravinda M de Silva / Lakshmanane Premkumar /
Abstract: We currently have an incomplete understanding of why only a fraction of human antibodies that bind to flaviviruses block infection of cells. Here we define the footprint of a strongly neutralizing ...We currently have an incomplete understanding of why only a fraction of human antibodies that bind to flaviviruses block infection of cells. Here we define the footprint of a strongly neutralizing human monoclonal antibody (mAb G9E) with Zika virus (ZIKV) by both X-ray crystallography and cryo-electron microscopy. Flavivirus envelope (E) glycoproteins are present as homodimers on the virion surface, and G9E bound to a quaternary structure epitope spanning both E protomers forming a homodimer. As G9E mainly neutralized ZIKV by blocking a step after viral attachment to cells, we tested if the neutralization mechanism of G9E was dependent on the mAb cross-linking E molecules and blocking low-pH triggered conformational changes required for viral membrane fusion. We introduced targeted mutations to the G9E paratope to create recombinant antibodies that bound to the ZIKV envelope without cross-linking E protomers. The G9E paratope mutants that bound to a restricted epitope on one protomer poorly neutralized ZIKV compared to the wild-type mAb, demonstrating that the neutralization mechanism depended on the ability of G9E to cross-link E proteins. In cell-free low pH triggered viral fusion assay, both wild-type G9E, and epitope restricted paratope mutant G9E bound to ZIKV but only the wild-type G9E blocked fusion. We propose that, beyond antibody binding strength, the ability of human antibodies to cross-link E-proteins is a critical determinant of flavivirus neutralization potency.
History
DepositionJun 28, 2022-
Header (metadata) releaseJan 4, 2023-
Map releaseJan 4, 2023-
UpdateJul 3, 2024-
Current statusJul 3, 2024Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_33718.png

Downloads & links

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Map

FileDownload / File: emd_33718.map.gz / Format: CCP4 / Size: 290.8 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.71 Å
Density
Contour LevelBy AUTHOR: 3.5
Minimum - Maximum-2.5877693 - 6.7733383
Average (Standard dev.)-0.000000006707957 (±1.0)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin-212-212-212
Dimensions424424424
Spacing424424424
CellA=B=C: 725.04004 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_33718_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_33718_half_map_2.map
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 ZIKV/H. sapiens/FrenchPolynesia/10087PF/2013

EntireName: Zika virus ZIKV/H. sapiens/FrenchPolynesia/10087PF/2013
Components
  • Complex: Zika virus ZIKV/H. sapiens/FrenchPolynesia/10087PF/2013
    • Complex: Zika virus ZIKV/H.
      • Protein or peptide: E protein
      • Protein or peptide: M protein
    • Complex: heavy chain, light chain
      • Protein or peptide: light chain
    • Protein or peptide: heavy chain

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Supramolecule #1: Zika virus ZIKV/H. sapiens/FrenchPolynesia/10087PF/2013

SupramoleculeName: Zika virus ZIKV/H. sapiens/FrenchPolynesia/10087PF/2013
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Zika virus ZIKV/H. sapiens/FrenchPolynesia/10087PF/2013

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Supramolecule #2: Zika virus ZIKV/H.

SupramoleculeName: Zika virus ZIKV/H. / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #3-#4
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #3: heavy chain, light chain

SupramoleculeName: heavy chain, light chain / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #2

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Macromolecule #1: heavy chain

MacromoleculeName: heavy chain / type: protein_or_peptide / ID: 1 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 24.694539 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: RVHLVESGGG VVQPGRSLRL SCVASGFAFS NYHMHWVRQA PGKGLEWVAI IWDDGSDQYY ADSVKGRFTI SRDNSKNTLF LQMNRLRAE DTALYYCVGG SSAYNGDNGW REAASLDDWG QGTLVTVSSA STKGPSVFPL APSSKSTSGG TAALGCLVKD Y FPEPVTVS ...String:
RVHLVESGGG VVQPGRSLRL SCVASGFAFS NYHMHWVRQA PGKGLEWVAI IWDDGSDQYY ADSVKGRFTI SRDNSKNTLF LQMNRLRAE DTALYYCVGG SSAYNGDNGW REAASLDDWG QGTLVTVSSA STKGPSVFPL APSSKSTSGG TAALGCLVKD Y FPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKKVEP KSC

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Macromolecule #2: light chain

MacromoleculeName: light chain / type: protein_or_peptide / ID: 2 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 22.58192 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: SALTQPASVS GSPGQSITIF CSGSSNDVGG YNYVSWYQQY PGKVPKLLIY DVNSRPSGVS NRFSGSKSGN TASLTISGLQ AEDEADYYC SSYTSRRTWV FGGGTIVTVL GQPKANPTVT LFPPSSEELQ ANKATLVCLI SDFYPGAVTV AWKADGSPVK A GVETTKPS ...String:
SALTQPASVS GSPGQSITIF CSGSSNDVGG YNYVSWYQQY PGKVPKLLIY DVNSRPSGVS NRFSGSKSGN TASLTISGLQ AEDEADYYC SSYTSRRTWV FGGGTIVTVL GQPKANPTVT LFPPSSEELQ ANKATLVCLI SDFYPGAVTV AWKADGSPVK A GVETTKPS KQSNNKYAAS SYLSLTPEQW KSHRSYSCQV THEGSTVEKT VAPT

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Macromolecule #3: E protein

MacromoleculeName: E protein / type: protein_or_peptide / ID: 3 / Number of copies: 3 / Enantiomer: LEVO / EC number: flavivirin
Source (natural)Organism: Zika virus ZIKV/H. sapiens/FrenchPolynesia/10087PF/2013
Strain: isolate ZIKV/Human/French Polynesia/10087PF/2013
Molecular weightTheoretical: 54.444051 KDa
Recombinant expressionOrganism: Aedes albopictus C6/36 cell densovirus
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

UniProtKB: Genome polyprotein

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Macromolecule #4: M protein

MacromoleculeName: M protein / 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: 8.388786 KDa
Recombinant expressionOrganism: Aedes albopictus C6/36 cell densovirus
SequenceString:
AVTLPSHSTR KLQTRSQTWL ESREYTKHLI RVENWIFRNP GFALAAAAIA WLLGSSTSQK VIYLVMILLI APAAA

UniProtKB: Genome polyprotein

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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
Sugar embeddingMaterial: ice
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: FEI FALCON II (4k x 4k) / Average electron dose: 25.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 5.7 µm / Nominal defocus min: 3.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: EMDB MAP
EMDB ID:

8139

Final reconstructionResolution.type: BY AUTHOR / Resolution: 5.9 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 4465
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: RIGID BODY FIT / Overall B value: 258
Output model

PDB-7yar:
ZIKV_Fab_G9E

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