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- PDB-5uhy: A Human Antibody Against Zika Virus Crosslinks the E Protein to P... -

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Basic information

Entry
Database: PDB / ID: 5uhy
TitleA Human Antibody Against Zika Virus Crosslinks the E Protein to Prevent Infection
Components
  • ZV67 Fab chain 1
  • ZV67 Fab chain 2
  • envelope proteinViral envelope
KeywordsVIRUS/IMMUNE SYSTEM / flavivirus / Zika / human antibody / therapeutic / VIRUS-IMMUNE SYSTEM complex
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 / viral capsid / nucleoside-triphosphate phosphatase / double-stranded RNA binding / 4 iron, 4 sulfur cluster binding / mRNA (guanine-N7)-methyltransferase ...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 / 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 / membrane => GO:0016020 / molecular adaptor activity / host cell endoplasmic reticulum membrane / host cell perinuclear region of cytoplasm / protein dimerization activity / RNA helicase / induction by virus of host autophagy / RNA-directed RNA polymerase / viral RNA genome replication / RNA-dependent RNA polymerase activity / serine-type endopeptidase activity / centrosome / fusion of virus membrane with host endosome membrane / 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 region / ATP binding / membrane / metal ion binding
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 / 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 / Envelope protein E
Similarity search - Component
Biological speciesHomo sapiens (human)
Zika virus
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 6.2 Å
AuthorsHasan, S.S. / Miller, A. / Sapparapu, G. / Fernandez, E. / Klose, T. / Long, F. / Fokine, A. / Porta, J.C. / Jiang, W. / Diamond, M.S. ...Hasan, S.S. / Miller, A. / Sapparapu, G. / Fernandez, E. / Klose, T. / Long, F. / Fokine, A. / Porta, J.C. / Jiang, W. / Diamond, M.S. / Crowe Jr., J.E. / Kuhn, R.J. / Rossmann, M.G.
Funding support United States, 4items
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
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)AI104972 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)HHSN272201400024C United States
CitationJournal: Nat Commun / Year: 2017
Title: A human antibody against Zika virus crosslinks the E protein to prevent infection.
Authors: S Saif Hasan / Andrew Miller / Gopal Sapparapu / Estefania Fernandez / Thomas Klose / Feng Long / Andrei Fokine / Jason C Porta / Wen Jiang / Michael S Diamond / James E Crowe / Richard J ...Authors: S Saif Hasan / Andrew Miller / Gopal Sapparapu / Estefania Fernandez / Thomas Klose / Feng Long / Andrei Fokine / Jason C Porta / Wen Jiang / Michael S Diamond / James E Crowe / Richard J Kuhn / Michael G Rossmann /
Abstract: The recent Zika virus (ZIKV) epidemic has been linked to unusual and severe clinical manifestations including microcephaly in fetuses of infected pregnant women and Guillian-Barré syndrome in adults. ...The recent Zika virus (ZIKV) epidemic has been linked to unusual and severe clinical manifestations including microcephaly in fetuses of infected pregnant women and Guillian-Barré syndrome in adults. Neutralizing antibodies present a possible therapeutic approach to prevent and control ZIKV infection. Here we present a 6.2 Å resolution three-dimensional cryo-electron microscopy (cryoEM) structure of an infectious ZIKV (strain H/PF/2013, French Polynesia) in complex with the Fab fragment of a highly therapeutic and neutralizing human monoclonal antibody, ZIKV-117. The antibody had been shown to prevent fetal infection and demise in mice. The structure shows that ZIKV-117 Fabs cross-link the monomers within the surface E glycoprotein dimers as well as between neighbouring dimers, thus preventing the reorganization of E protein monomers into fusogenic trimers in the acidic environment of endosomes.
History
DepositionJan 12, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 29, 2017Provider: repository / Type: Initial release
Revision 1.1Sep 13, 2017Group: Author supporting evidence / Data collection / Category: em_software / pdbx_audit_support
Item: _em_software.name / _pdbx_audit_support.funding_organization
Revision 1.2Jul 18, 2018Group: Data collection / Category: em_software / Item: _em_software.name
Revision 1.3Nov 27, 2019Group: Author supporting evidence / Category: pdbx_audit_support
Item: _pdbx_audit_support.funding_organization / _pdbx_audit_support.grant_number

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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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  • Deposited structure unit
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  • Simplified surface model + fitted atomic model
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Structure viewerMolecule:
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Assembly

Deposited unit
G: ZV67 Fab chain 1
H: ZV67 Fab chain 2
I: ZV67 Fab chain 1
J: ZV67 Fab chain 2
C: envelope protein
E: envelope protein
A: envelope protein


Theoretical massNumber of molelcules
Total (without water)222,8387
Polymers222,8387
Non-polymers00
Water0
1
G: ZV67 Fab chain 1
H: ZV67 Fab chain 2
I: ZV67 Fab chain 1
J: ZV67 Fab chain 2
C: envelope protein
E: envelope protein
A: envelope protein
x 60


Theoretical massNumber of molelcules
Total (without water)13,370,253420
Polymers13,370,253420
Non-polymers00
Water0
TypeNameSymmetry operationNumber
point symmetry operation60
2


  • Idetical with deposited unit in distinct coordinate
  • icosahedral asymmetric unit
TypeNameSymmetry operationNumber
point symmetry operation1
3
G: ZV67 Fab chain 1
H: ZV67 Fab chain 2
I: ZV67 Fab chain 1
J: ZV67 Fab chain 2
C: envelope protein
E: envelope protein
A: envelope protein
x 5


  • icosahedral pentamer
  • 1.11 MDa, 35 polymers
Theoretical massNumber of molelcules
Total (without water)1,114,18835
Polymers1,114,18835
Non-polymers00
Water0
TypeNameSymmetry operationNumber
point symmetry operation5
4
G: ZV67 Fab chain 1
H: ZV67 Fab chain 2
I: ZV67 Fab chain 1
J: ZV67 Fab chain 2
C: envelope protein
E: envelope protein
A: envelope protein
x 6


  • icosahedral 23 hexamer
  • 1.34 MDa, 42 polymers
Theoretical massNumber of molelcules
Total (without water)1,337,02542
Polymers1,337,02542
Non-polymers00
Water0
TypeNameSymmetry operationNumber
point symmetry operation6
5


  • Idetical with deposited unit in distinct coordinate
  • icosahedral asymmetric unit, std point frame
TypeNameSymmetry operationNumber
transform to point frame1
SymmetryPoint symmetry: (Schoenflies symbol: I (icosahedral))

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Components

#1: Antibody ZV67 Fab chain 1


Mass: 23658.074 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#2: Antibody ZV67 Fab chain 2


Mass: 23074.842 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#3: Protein envelope protein / Viral envelope / E


Mass: 43123.906 Da / Num. of mol.: 3 / Fragment: ectodomain (UNP residues 1-396)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Zika virus / Production host: Cricetinae gen. sp. (mammal) / References: UniProt: A0A120IIH7, UniProt: A0A024B7W1*PLUS

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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

ComponentName: Zika virus with ZIKV117 Fab / Type: COMPLEX / Entity ID: all / Source: MULTIPLE SOURCES
Molecular weightExperimental value: NO
Source (natural)Organism: Zika virus
Details of virusEmpty: NO / Enveloped: YES / Isolate: SPECIES / Type: VIRION
Natural hostOrganism: Homo sapiens
Buffer solutionpH: 7.5
Buffer component
IDConc.NameFormulaBuffer-ID
130 mMTrizmaC4H11NO31
2120 mMsodium chlorideNaClSodium chloride1
31 mMEDTAEthylenediaminetetraacetic acid1
SpecimenConc.: 1 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES / Details: 1 mg/mL E protein
Specimen supportDetails: no pretreatment / Grid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Ted Pella 01824
VitrificationInstrument: GATAN CRYOPLUNGE 3 / Cryogen name: ETHANE / Humidity: 80 % / Chamber temperature: 293 K
Details: 2.5 uL of sample was deposited on the carbon layer, with double-sided blotting applied twice for 5-6 seconds.

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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 FIELDBright-field microscopy / Nominal magnification: 18000 X / Cs: 2.7 mm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingAverage exposure time: 11 sec. / Electron dose: 32.6 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 1140
Image scansWidth: 3838 / Height: 3710 / Movie frames/image: 55

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Processing

EM software
IDNameVersionCategory
1FindEM2particle selection
2Appion3.2particle selection
3Leginon3.2image acquisition
5Appion3.2CTF correction
6CTFFIND3CTF correction
9EMfitmodel fitting
10UCSF Chimeramodel fitting
12jsprinitial Euler assignment
13jsprfinal Euler assignment
14RELION1.4classification
15jspr3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: I (icosahedral)
3D reconstructionResolution: 6.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 8153 / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT

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