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- PDB-7kcr: Cryo-EM structure of Zika virus in complex with E protein cross-l... -

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Basic information

Entry
Database: PDB / ID: 7kcr
TitleCryo-EM structure of Zika virus in complex with E protein cross-linking human monoclonal antibody ADI30056
Components
  • ADI30056 Fab heavy chain variable region
  • ADI30056 Fab light chain variable region
  • envelope protein E
  • membrane protein MBiological membrane
KeywordsVIRUS/IMMUNE SYSTEM / Zika Virus / Flavivirus / Zika-Antibody / 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 / ribonucleoside triphosphate phosphatase activity / 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 / 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 / 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 / host cell endoplasmic reticulum membrane / host cell perinuclear region of cytoplasm / protein dimerization activity / molecular adaptor 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 / 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 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, chymotrypsin-like fold / Peptidase S1, PA clan / DNA/RNA polymerase superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Genome polyprotein / Core protein
Similarity search - Component
Biological speciesHomo sapiens (human)
Zika virus ZIKV/H. sapiens/FrenchPolynesia/10087PF/2013
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4 Å
AuthorsSevvana, M. / Rogers, T.F. / Miller, A.S. / Long, F. / Klose, T. / Beutler, N. / Lai, Y.C. / Parren, M. / Walker, L.M. / Buda, G. ...Sevvana, M. / Rogers, T.F. / Miller, A.S. / Long, F. / Klose, T. / Beutler, N. / Lai, Y.C. / Parren, M. / Walker, L.M. / Buda, G. / Burton, D.R. / Rossmann, M.G. / Kuhn, R.J.
Funding support United States, 2items
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
CitationJournal: Viruses / Year: 2020
Title: Structural Basis of Zika Virus Specific Neutralization in Subsequent Flavivirus Infections.
Authors: Madhumati Sevvana / Thomas F Rogers / Andrew S Miller / Feng Long / Thomas Klose / Nathan Beutler / Yen-Chung Lai / Mara Parren / Laura M Walker / Geeta Buda / Dennis R Burton / Michael G ...Authors: Madhumati Sevvana / Thomas F Rogers / Andrew S Miller / Feng Long / Thomas Klose / Nathan Beutler / Yen-Chung Lai / Mara Parren / Laura M Walker / Geeta Buda / Dennis R Burton / Michael G Rossmann / Richard J Kuhn /
Abstract: Zika virus (ZIKV), a mosquito-borne human flavivirus that causes microcephaly and other neurological disorders, has been a recent focus for the development of flavivirus vaccines and therapeutics. We ...Zika virus (ZIKV), a mosquito-borne human flavivirus that causes microcephaly and other neurological disorders, has been a recent focus for the development of flavivirus vaccines and therapeutics. We report here a 4.0 Å resolution structure of the mature ZIKV in complex with ADI-30056, a ZIKV-specific human monoclonal antibody (hMAb) isolated from a ZIKV infected donor with a prior dengue virus infection. The structure shows that the hMAb interactions span across the E protein dimers on the virus surface, inhibiting conformational changes required for the formation of infectious fusogenic trimers similar to the hMAb, ZIKV-117. Structure-based functional analysis, and structure and sequence comparisons, identified ZIKV residues essential for neutralization and crucial for the evolution of highly potent E protein crosslinking Abs in ZIKV. Thus, this epitope, ZIKV's "Achilles heel", defined by the contacts between ZIKV and ADI-30056, could be a suitable target for the design of therapeutic antibodies.
History
DepositionOct 7, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 16, 2020Provider: repository / Type: Initial release

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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
  • EMDB-22818
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  • Superimposition on EM map
  • EMDB-22818
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Structure viewerMolecule:
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Assembly

Deposited unit
H: ADI30056 Fab heavy chain variable region
L: ADI30056 Fab light chain variable region
A: envelope protein E
B: membrane protein M
C: envelope protein E
D: membrane protein M
E: envelope protein E
F: membrane protein M
hetero molecules


Theoretical massNumber of molelcules
Total (without water)214,17711
Polymers212,9048
Non-polymers1,2733
Water0
1
H: ADI30056 Fab heavy chain variable region
L: ADI30056 Fab light chain variable region
A: envelope protein E
B: membrane protein M
C: envelope protein E
D: membrane protein M
E: envelope protein E
F: membrane protein M
hetero molecules
x 60


Theoretical massNumber of molelcules
Total (without water)12,850,612660
Polymers12,774,220480
Non-polymers76,392180
Water0
TypeNameSymmetry operationNumber
point symmetry operation60
2


  • Idetical with deposited unit in distinct coordinate
  • icosahedral asymmetric unit
TypeNameSymmetry operationNumber
point symmetry operation1
3
H: ADI30056 Fab heavy chain variable region
L: ADI30056 Fab light chain variable region
A: envelope protein E
B: membrane protein M
C: envelope protein E
D: membrane protein M
E: envelope protein E
F: membrane protein M
hetero molecules
x 5


  • icosahedral pentamer
  • 1.07 MDa, 40 polymers
Theoretical massNumber of molelcules
Total (without water)1,070,88455
Polymers1,064,51840
Non-polymers6,36615
Water0
TypeNameSymmetry operationNumber
point symmetry operation5
4
H: ADI30056 Fab heavy chain variable region
L: ADI30056 Fab light chain variable region
A: envelope protein E
B: membrane protein M
C: envelope protein E
D: membrane protein M
E: envelope protein E
F: membrane protein M
hetero molecules
x 6


  • icosahedral 23 hexamer
  • 1.29 MDa, 48 polymers
Theoretical massNumber of molelcules
Total (without water)1,285,06166
Polymers1,277,42248
Non-polymers7,63918
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 ADI30056 Fab heavy chain variable region


Mass: 13467.001 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Scheffersomyces stipitis (fungus)
#2: Antibody ADI30056 Fab light chain variable region


Mass: 11385.728 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Scheffersomyces stipitis (fungus)
#3: Protein envelope protein E /


Mass: 54186.762 Da / Num. of mol.: 3 / Fragment: UNP residues 291-791
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Zika virus ZIKV/H. sapiens/FrenchPolynesia/10087PF/2013
Production host: Zika virus ZIKV/H. sapiens/FrenchPolynesia/10087PF/2013
References: UniProt: A0A678Z1Y6, UniProt: A0A024B7W1*PLUS
#4: Protein membrane protein M / Biological membrane


Mass: 8496.883 Da / Num. of mol.: 3 / Fragment: UNP residues 216-290
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Zika virus ZIKV/H. sapiens/FrenchPolynesia/10087PF/2013
Production host: Zika virus ZIKV/H. sapiens/FrenchPolynesia/10087PF/2013
References: UniProt: A0A678Z1Y6, UniProt: A0A024B7W1*PLUS
#5: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}LINUCSPDB-CARE
Has ligand of interestN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: 2D ARRAY / 3D reconstruction method: single particle reconstruction

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Sample preparation

Component
IDNameTypeEntity IDParent-IDSource
1Zika virus in complex with monoclonal antibody ADI30056COMPLEX#1-#40MULTIPLE SOURCES
2Zika virus ZIKV/H. sapiens/FrenchPolynesia/10087PF/2013VIRUS#3-#41RECOMBINANT
3monoclonal antibody ADI30056COMPLEX#1-#21RECOMBINANT
Molecular weightValue: 15 MDa / Experimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
12Zika virus ZIKV/H. sapiens/FrenchPolynesia/10087PF/20132043570
23Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
12Zika virus ZIKV/H. sapiens/FrenchPolynesia/10087PF/20132043570
23Scheffersomyces stipitis (fungus)4924
Details of virusEmpty: NO / Enveloped: YES / Isolate: STRAIN / Type: VIRION
Natural hostOrganism: Homo sapiens
Virus shellName: Envelope protein shell / Diameter: 500 nm / Triangulation number (T number): 3
Buffer solutionpH: 7.5
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: OTHER
Electron lensMode: BRIGHT FIELDBright-field microscopy / C2 aperture diameter: 100 µm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 30 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.16_3549: / Classification: refinement
EM software
IDNameVersionCategory
1FindEMparticle selection
2Leginonimage acquisition
4CTFFIND4CTF correction
7Cootmodel fitting
9jsprinitial Euler assignment
10jsprfinal Euler assignment
11RELIONclassification
12jspr3D reconstruction
13PHENIXmodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 165789
SymmetryPoint symmetry: I (icosahedral)
3D reconstructionResolution: 4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 22330 / Algorithm: FOURIER SPACE / Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT / Space: REAL
Atomic model buildingPDB-ID: 6CO8

6co8

Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00815329
ELECTRON MICROSCOPYf_angle_d0.99720767
ELECTRON MICROSCOPYf_dihedral_angle_d17.6929012
ELECTRON MICROSCOPYf_chiral_restr0.0572353
ELECTRON MICROSCOPYf_plane_restr0.0072625

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