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- PDB-5h32: Cryo-EM structure of zika virus complexed with Fab C10 at pH 5.0 -

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Basic information

Entry
Database: PDB / ID: 5h32
TitleCryo-EM structure of zika virus complexed with Fab C10 at pH 5.0
Components
  • C10 IgG heavy chain variable region
  • C10 IgG light chain variable region
  • structural protein E
KeywordsVIRUS/IMMUNE SYSTEM / 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 / viral capsid / double-stranded RNA binding / nucleoside-triphosphate phosphatase / 4 iron, 4 sulfur cluster binding / clathrin-dependent endocytosis of virus by host cell ...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 / viral capsid / double-stranded RNA binding / nucleoside-triphosphate phosphatase / 4 iron, 4 sulfur cluster binding / clathrin-dependent endocytosis of virus by host cell / molecular adaptor activity / mRNA (guanine-N7)-methyltransferase / methyltransferase cap1 / 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 type I interferon-mediated signaling pathway / 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 / viral envelope / lipid binding / 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 capsid protein C superfamily / Flavivirus non-structural protein NS2B / 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 capsid protein C superfamily / Flavivirus non-structural protein NS2B / 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
Biological speciesHomo sapiens (human)
Zika virus
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 12 Å
AuthorsZhang, S. / Kostyuchenko, V. / Ng, T.-S. / Lok, S.-M.
Funding support Singapore, United States, 3items
OrganizationGrant numberCountry
Ministry of Education Tier 3 grantMOE2012-T3-1-008 Singapore
National Research Foundation Investigatorship awardNRF-NRFI2016-01 Singapore
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)AI100625 and AI 107731 United States
CitationJournal: Nat Commun / Year: 2016
Title: Neutralization mechanism of a highly potent antibody against Zika virus.
Authors: Shuijun Zhang / Victor A Kostyuchenko / Thiam-Seng Ng / Xin-Ni Lim / Justin S G Ooi / Sebastian Lambert / Ter Yong Tan / Douglas G Widman / Jian Shi / Ralph S Baric / Shee-Mei Lok /
Abstract: The rapid spread of Zika virus (ZIKV), which causes microcephaly and Guillain-Barré syndrome, signals an urgency to identify therapeutics. Recent efforts to rescreen dengue virus human antibodies ...The rapid spread of Zika virus (ZIKV), which causes microcephaly and Guillain-Barré syndrome, signals an urgency to identify therapeutics. Recent efforts to rescreen dengue virus human antibodies for ZIKV cross-neutralization activity showed antibody C10 as one of the most potent. To investigate the ability of the antibody to block fusion, we determined the cryoEM structures of the C10-ZIKV complex at pH levels mimicking the extracellular (pH8.0), early (pH6.5) and late endosomal (pH5.0) environments. The 4.0 Å resolution pH8.0 complex structure shows that the antibody binds to E proteins residues at the intra-dimer interface, and the virus quaternary structure-dependent inter-dimer and inter-raft interfaces. At pH6.5, antibody C10 locks all virus surface E proteins, and at pH5.0, it locks the E protein raft structure, suggesting that it prevents the structural rearrangement of the E proteins during the fusion event-a vital step for infection. This suggests antibody C10 could be a good therapeutic candidate.
History
DepositionOct 20, 2016Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Nov 30, 2016Provider: repository / Type: Initial release
Revision 1.1Jan 25, 2017Group: Database references
Revision 1.2Mar 23, 2022Group: Author supporting evidence / Data collection ...Author supporting evidence / Data collection / Database references / Derived calculations
Category: database_2 / em_image_scans ...database_2 / em_image_scans / pdbx_audit_support / pdbx_struct_oper_list
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_audit_support.funding_organization / _pdbx_struct_oper_list.name / _pdbx_struct_oper_list.symmetry_operation / _pdbx_struct_oper_list.type
Revision 1.3May 29, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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Structure visualization

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  • Biological unit as complete icosahedral assembly
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  • Biological unit as icosahedral pentamer
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  • Biological unit as icosahedral 23 hexamer
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Assembly

Deposited unit
A: structural protein E
C: structural protein E
B: structural protein E
G: C10 IgG heavy chain variable region
H: C10 IgG light chain variable region
K: C10 IgG heavy chain variable region
L: C10 IgG light chain variable region
I: C10 IgG heavy chain variable region
M: C10 IgG light chain variable region


Theoretical massNumber of molelcules
Total (without water)209,5669
Polymers209,5669
Non-polymers00
Water00
1
A: structural protein E
C: structural protein E
B: structural protein E
G: C10 IgG heavy chain variable region
H: C10 IgG light chain variable region
K: C10 IgG heavy chain variable region
L: C10 IgG light chain variable region
I: C10 IgG heavy chain variable region
M: C10 IgG light chain variable region
x 60


Theoretical massNumber of molelcules
Total (without water)12,573,963540
Polymers12,573,963540
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
A: structural protein E
C: structural protein E
B: structural protein E
G: C10 IgG heavy chain variable region
H: C10 IgG light chain variable region
K: C10 IgG heavy chain variable region
L: C10 IgG light chain variable region
I: C10 IgG heavy chain variable region
M: C10 IgG light chain variable region
x 5


  • icosahedral pentamer
  • 1.05 MDa, 45 polymers
Theoretical massNumber of molelcules
Total (without water)1,047,83045
Polymers1,047,83045
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
point symmetry operation4
4
A: structural protein E
C: structural protein E
B: structural protein E
G: C10 IgG heavy chain variable region
H: C10 IgG light chain variable region
K: C10 IgG heavy chain variable region
L: C10 IgG light chain variable region
I: C10 IgG heavy chain variable region
M: C10 IgG light chain variable region
x 6


  • icosahedral 23 hexamer
  • 1.26 MDa, 54 polymers
Theoretical massNumber of molelcules
Total (without water)1,257,39654
Polymers1,257,39654
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
point symmetry operation5
5


  • Idetical with deposited unit in distinct coordinate
  • icosahedral asymmetric unit, std point frame
TypeNameSymmetry operationNumber
transform to point frame1
6
A: structural protein E
C: structural protein E
B: structural protein E
G: C10 IgG heavy chain variable region
H: C10 IgG light chain variable region
K: C10 IgG heavy chain variable region
L: C10 IgG light chain variable region
I: C10 IgG heavy chain variable region
M: C10 IgG light chain variable region
x 60


  • crystal asymmetric unit, crystal frame
  • 12.6 MDa, 540 polymers
Theoretical massNumber of molelcules
Total (without water)12,573,963540
Polymers12,573,963540
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z2
point symmetry operation59
SymmetryPoint symmetry: (Schoenflies symbol: I (icosahedral))

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Components

#1: Protein structural protein E / Coordinate model: Cα atoms only


Mass: 44069.930 Da / Num. of mol.: 3 / Source method: isolated from a natural source / Source: (natural) Zika virus / Strain: Mr 766 / References: UniProt: A0A024B7W1
#2: Antibody C10 IgG heavy chain variable region / Coordinate model: Cα atoms only


Mass: 14487.058 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): HEK293T / Production host: Homo sapiens (human)
#3: Antibody C10 IgG light chain variable region / Coordinate model: Cα atoms only


Mass: 11298.362 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): HEK293T / Production host: Homo sapiens (human)

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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 complexed with Fab C10 at pH 5.0COMPLEXall0MULTIPLE SOURCES
2zika virusCOMPLEX#11NATURAL
3Fab C10COMPLEX#2-#31RECOMBINANT
Source (natural)Organism: Zika virus
Source (recombinant)Organism: Homo sapiens (human) / Cell: HEK293T / Plasmid: unknown
Buffer solutionpH: 5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
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
Image recordingElectron dose: 20 e/Å2 / Film or detector model: FEI FALCON II (4k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 12 Å / Resolution method: FSC 0.5 CUT-OFF / Num. of particles: 23810 / Symmetry type: POINT

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