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- PDB-7yar: ZIKV_Fab_G9E -

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Basic information

Entry
Database: PDB / ID: 7yar
TitleZIKV_Fab_G9E
Components
  • E protein
  • M protein
  • heavy chain
  • light chain
KeywordsVIRUS / virus complexed with antibody
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 / 4 iron, 4 sulfur cluster binding ...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
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 5.9 Å
AuthorsShu, B. / Thiam-Seng, N. / Lok, S.
Funding support Singapore, 3items
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, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jan 4, 2023Provider: repository / Type: Initial release
Revision 1.1Feb 8, 2023Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Aug 2, 2023Group: Other / Category: pdbx_database_status / Item: _pdbx_database_status.pdb_format_compatible
Revision 1.3Jul 3, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond / em_admin / Item: _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
I: heavy chain
H: light chain
G: heavy chain
M: light chain
A: E protein
C: E protein
D: M protein
F: M protein
K: heavy chain
L: light chain
B: E protein
E: M protein


Theoretical massNumber of molelcules
Total (without water)330,32812
Polymers330,32812
Non-polymers00
Water00
1
I: heavy chain
H: light chain
G: heavy chain
M: light chain
A: E protein
C: E protein
D: M protein
F: M protein
K: heavy chain
L: light chain
B: E protein
E: M protein
x 60


Theoretical massNumber of molelcules
Total (without water)19,819,673720
Polymers19,819,673720
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
point symmetry operation59
2


  • Idetical with deposited unit
  • icosahedral asymmetric unit
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
I: heavy chain
H: light chain
G: heavy chain
M: light chain
A: E protein
C: E protein
D: M protein
F: M protein
K: heavy chain
L: light chain
B: E protein
E: M protein
x 5


  • icosahedral pentamer
  • 1.65 MDa, 60 polymers
Theoretical massNumber of molelcules
Total (without water)1,651,63960
Polymers1,651,63960
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
point symmetry operation4
4
I: heavy chain
H: light chain
G: heavy chain
M: light chain
A: E protein
C: E protein
D: M protein
F: M protein
K: heavy chain
L: light chain
B: E protein
E: M protein
x 6


  • icosahedral 23 hexamer
  • 1.98 MDa, 72 polymers
Theoretical massNumber of molelcules
Total (without water)1,981,96772
Polymers1,981,96772
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
point symmetry operation5
5


  • Idetical with deposited unit
  • icosahedral asymmetric unit, std point frame
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
SymmetryPoint symmetry: (Schoenflies symbol: I (icosahedral))

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Components

#1: Antibody heavy chain / Coordinate model: Cα atoms only


Mass: 24694.539 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#2: Antibody light chain / Coordinate model: Cα atoms only


Mass: 22581.920 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#3: Protein E protein / Coordinate model: Cα atoms only


Mass: 54444.051 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Zika virus ZIKV/H. sapiens/FrenchPolynesia/10087PF/2013
Strain: isolate ZIKV/Human/French Polynesia/10087PF/2013 / Production host: Aedes albopictus C6/36 cell densovirus
References: UniProt: A0A024B7W1, flavivirin, nucleoside-triphosphate phosphatase, RNA helicase, mRNA (guanine-N7)-methyltransferase, methyltransferase cap1, RNA-directed RNA polymerase
#4: Protein M protein / Coordinate model: Cα atoms only


Mass: 8388.786 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Zika virus ZIKV/H. sapiens/FrenchPolynesia/10087PF/2013
Production host: Aedes albopictus C6/36 cell densovirus / References: UniProt: A0A1V0E2H4

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

Component
IDNameTypeEntity IDParent-IDSource
1Zika virus ZIKV/H. sapiens/FrenchPolynesia/10087PF/2013COMPLEXall0MULTIPLE SOURCES
2Zika virus ZIKV/H.COMPLEX#3-#41RECOMBINANT
3heavy chain, light chainCOMPLEX#2, #21RECOMBINANT
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
21Zika virus ZIKV/H. sapiens/FrenchPolynesia/10087PF/20132043570
32Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
11Aedes albopictus C6/36 cell densovirus194675
22Homo sapiens (human)9606
Details of virusEmpty: NO / Enveloped: YES / Isolate: STRAIN / Type: VIRION
Buffer solutionpH: 8
SpecimenEmbedding applied: YES / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
EM embeddingMaterial: ice
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 5700 nm / Nominal defocus min: 3000 nm
Image recordingElectron dose: 25 e/Å2 / Film or detector model: FEI FALCON II (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.20.1_4487: / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 5.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 4465 / Symmetry type: POINT
Atomic model buildingB value: 258 / Protocol: RIGID BODY FIT / Space: REAL
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00323746
ELECTRON MICROSCOPYf_angle_d0.72232256
ELECTRON MICROSCOPYf_dihedral_angle_d6.2753282
ELECTRON MICROSCOPYf_chiral_restr0.0443644
ELECTRON MICROSCOPYf_plane_restr0.0054104

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