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- EMDB-6793: Cryo-EM structure of zika virus complexed with Fab of ZKA190 at p... -

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Entry
Database: EMDB / ID: 6793
TitleCryo-EM structure of zika virus complexed with Fab of ZKA190 at pH 8.0 and 37 celsius degree
Map dataZika virus complexed with the Fab molecule of a human monoclonal antibody named ZKA190
Samplezika virus complexed with Fab of a human monoclonal antibody named ZKA190
  • zika virus
  • Fab ZKA190
  • protein E
  • (variable region of Fab ZKA190 ...) x 2
Function / homologyFlavivirus non-structural protein NS4B / Flavivirus non-structural protein NS4A / S-adenosyl-L-methionine-dependent methyltransferase / P-loop containing nucleoside triphosphate hydrolase / Flavivirus glycoprotein E, immunoglobulin-like domain / mRNA cap 0/1 methyltransferase / Flavivirus envelope glycoprotein E, Stem/Anchor domain / Immunoglobulin E-set / Genome polyprotein, Flavivirus / Helicase superfamily 1/2, ATP-binding domain ...Flavivirus non-structural protein NS4B / Flavivirus non-structural protein NS4A / S-adenosyl-L-methionine-dependent methyltransferase / P-loop containing nucleoside triphosphate hydrolase / Flavivirus glycoprotein E, immunoglobulin-like domain / mRNA cap 0/1 methyltransferase / Flavivirus envelope glycoprotein E, Stem/Anchor domain / Immunoglobulin E-set / Genome polyprotein, Flavivirus / Helicase superfamily 1/2, ATP-binding domain / Envelope glycoprotein M, flavivirus / RNA-directed RNA polymerase, flavivirus / Flavivirus/Alphavirus glycoprotein, immunoglobulin-like domain superfamily / Flavivirus non-structural protein NS2B / Flavivirus capsid protein C superfamily / Flavivirus non-structural protein NS2A / Flavivirus capsid protein C / Flavivirus non-structural protein NS1 / Flaviviral glycoprotein E, central domain, subdomain 2 / Helicase, C-terminal / Flavivirus NS3, petidase S7 / Flavivirus polyprotein propeptide / Ribosomal RNA methyltransferase FtsJ domain / RNA-directed RNA polymerase, catalytic domain / Peptidase S1, PA clan / DEAD box, Flavivirus / Flavivirus glycoprotein, central and dimerisation domain superfamily / Flavivirus glycoprotein central and dimerisation domain / Flaviviral glycoprotein E, central domain, subdomain 1 / Flaviviral glycoprotein E, dimerisation domain / mRNA cap 0 and cap 1 methyltransferase (EC 2.1.1.56 and EC 2.1.1.57) domain profile. / Flavivirus NS3 protease (NS3pro) domain profile. / Flavivirus NS2B domain profile. / Superfamilies 1 and 2 helicase C-terminal domain profile. / Superfamilies 1 and 2 helicase ATP-binding type-1 domain profile. / RdRp of positive ssRNA viruses catalytic domain profile. / Flavivirus DEAD domain / Flavivirus glycoprotein, immunoglobulin-like domain / FtsJ-like methyltransferase / Flavivirus polyprotein propeptide / Flavivirus non-structural protein NS4A / Flavivirus non-structural protein NS4B / Flavivirus non-structural protein NS2A / Flavivirus envelope glycoprotein M / Flavivirus capsid protein C / Flavivirus non-structural protein NS2B / Flavivirus RNA-directed RNA polymerase / Peptidase S7, Flavivirus NS3 serine protease / Flavivirus non-structural Protein NS1 / Flavivirus glycoprotein, central and dimerisation domains / Flavivirus polyprotein propeptide superfamily / Flavivirus envelope glycoprotein E, Stem/Anchor domain superfamily / Envelope glycoprotein M superfamily, flavivirus / suppression by virus of host innate immune response / suppression by virus of host TYK2 activity / Flavivirin / mRNA (guanine-N7-)-methyltransferase / mRNA (nucleoside-2'-O-)-methyltransferase / suppression by virus of host STAT2 activity / mRNA (nucleoside-2'-O-)-methyltransferase activity / suppression by virus of host STAT1 activity / mRNA (guanine-N7-)-methyltransferase activity / host cell endoplasmic reticulum membrane / ATP-dependent helicase activity / host cell perinuclear region of cytoplasm / RNA helicase activity / double-stranded RNA binding / 4 iron, 4 sulfur cluster binding / suppression by virus of host type I interferon-mediated signaling pathway / RNA helicase / nucleoside-triphosphatase / viral capsid / RNA-directed RNA polymerase / induction by virus of host autophagy / clathrin-dependent endocytosis of virus by host cell / fusion of virus membrane with host endosome membrane / viral RNA genome replication / RNA-directed 5'-3' RNA polymerase activity / viral envelope / protein dimerization activity / virion attachment to host cell / host cell nucleus / GTP binding / virion membrane / structural molecule activity / serine-type endopeptidase activity / regulation of transcription, DNA-templated / transcription, DNA-templated / integral component of membrane / extracellular region / ATP binding / metal ion binding / Genome polyprotein / Genome polyprotein
Function and homology information
SourceZika virus
Methodsingle particle reconstruction / cryo EM / 22 Å resolution
AuthorsWang JQ / Lok SM
Citation
Journal: Cell / Year: 2017
Title: A Human Bi-specific Antibody against Zika Virus with High Therapeutic Potential.
Authors: Jiaqi Wang / Marco Bardelli / Diego A Espinosa / Mattia Pedotti / Thiam-Seng Ng / Siro Bianchi / Luca Simonelli / Elisa X Y Lim / Mathilde Foglierini / Fabrizia Zatta / Stefano Jaconi / Martina Beltramello / Elisabetta Cameroni / Guntur Fibriansah / Jian Shi / Taylor Barca / Isabel Pagani / Alicia Rubio / Vania Broccoli / Elisa Vicenzi / Victoria Graham / Steven Pullan / Stuart Dowall / Roger Hewson / Simon Jurt / Oliver Zerbe / Karin Stettler / Antonio Lanzavecchia / Federica Sallusto / Andrea Cavalli / Eva Harris / Shee-Mei Lok / Luca Varani / Davide Corti
Abstract: Zika virus (ZIKV), a mosquito-borne flavivirus, causes devastating congenital birth defects. We isolated a human monoclonal antibody (mAb), ZKA190, that potently cross-neutralizes multi-lineage ZIKV ...Zika virus (ZIKV), a mosquito-borne flavivirus, causes devastating congenital birth defects. We isolated a human monoclonal antibody (mAb), ZKA190, that potently cross-neutralizes multi-lineage ZIKV strains. ZKA190 is highly effective in vivo in preventing morbidity and mortality of ZIKV-infected mice. NMR and cryo-electron microscopy show its binding to an exposed epitope on DIII of the E protein. ZKA190 Fab binds all 180 E protein copies, altering the virus quaternary arrangement and surface curvature. However, ZIKV escape mutants emerged in vitro and in vivo in the presence of ZKA190, as well as of other neutralizing mAbs. To counter this problem, we developed a bispecific antibody (FIT-1) comprising ZKA190 and a second mAb specific for DII of E protein. In addition to retaining high in vitro and in vivo potencies, FIT-1 robustly prevented viral escape, warranting its development as a ZIKV immunotherapy.
#1: Journal: To Be Published
Title: Cryo-EM structure of zika virus complexed with a human monoclonal antibody
Authors: Wang JQ / Lok SM
Validation ReportPDB-ID: 5y0a

SummaryFull reportAbout validation report
DateDeposition: Jul 15, 2017 / Header (metadata) release: Oct 4, 2017 / Map release: Oct 4, 2017 / Last update: Oct 4, 2017

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 1
  • Imaged by UCSF Chimera
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  • Surface view colored by radius
  • Surface level: 1
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  • Surface view with fitted model
  • Atomic models: : PDB-5y0a
  • Surface level: 1
  • Imaged by UCSF Chimera
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  • Simplified surface model + fitted atomic model
  • Atomic models: PDB-5y0a
  • Imaged by Jmol
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

Downloads & links

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Map

Fileemd_6793.map.gz (map file in CCP4 format, 32001 KB)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
200 pix
3.42 Å/pix.
= 684. Å
200 pix
3.42 Å/pix.
= 684. Å
200 pix
3.42 Å/pix.
= 684. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 3.42 Å
Density
Contour Level:1 (by author), 1 (movie #1):
Minimum - Maximum-3.5382104 - 6.161489
Average (Standard dev.)-3.623909E-9 (1)
Details

EMDB XML:

Space Group Number1
Map Geometry
Axis orderXYZ
Dimensions200200200
Origin-100-100-100
Limit999999
Spacing200200200
CellA=B=C: 684 Å
α=β=γ: 90 deg.

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z3.423.423.42
M x/y/z200200200
origin x/y/z0.0000.0000.000
length x/y/z684.000684.000684.000
α/β/γ90.00090.00090.000
start NX/NY/NZ
NX/NY/NZ
MAP C/R/S123
start NC/NR/NS-100-100-100
NC/NR/NS200200200
D min/max/mean-3.5386.161-0.000

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Supplemental data

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Sample components

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Entire zika virus complexed with Fab of a human monoclonal antibody name...

EntireName: zika virus complexed with Fab of a human monoclonal antibody named ZKA190
Number of components: 6

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Component #1: protein, zika virus complexed with Fab of a human monoclonal anti...

ProteinName: zika virus complexed with Fab of a human monoclonal antibody named ZKA190
Recombinant expression: No
SourceSpecies: Zika virus / Strain: Mr 766

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Component #2: protein, zika virus

ProteinName: zika virus / Recombinant expression: No

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Component #3: protein, Fab ZKA190

ProteinName: Fab ZKA190 / Recombinant expression: No

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Component #4: protein, protein E

ProteinName: protein E / Recombinant expression: No
MassTheoretical: 44.06993 kDa
Source (engineered)Expression System: Zika virus (strain Mr 766) / Strain: Mr 766

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Component #5: protein, variable region of Fab ZKA190 heavy chain

ProteinName: variable region of Fab ZKA190 heavy chain / Recombinant expression: No
MassTheoretical: 14.41001 kDa
Source (engineered)Expression System: Homo sapiens (human)

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Component #6: protein, variable region of Fab ZKA190 light chain

ProteinName: variable region of Fab ZKA190 light chain / Recombinant expression: No
MassTheoretical: 11.935241 kDa
Source (engineered)Expression System: Homo sapiens (human)

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Experimental details

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Sample preparation

SpecimenSpecimen state: particle / Method: cryo EM
Sample solutionSpecimen conc.: 1 mg/ml / pH: 8
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
ImagingMicroscope: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Electron dose: 20 e/Å2 / Illumination mode: FLOOD BEAM
LensCs: 2.7 mm / Imaging mode: BRIGHT FIELD
Specimen HolderModel: OTHER
CameraDetector: FEI FALCON II (4k x 4k)

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Image processing

ProcessingMethod: single particle reconstruction / Applied symmetry: I (icosahedral) / Number of projections: 6728
3D reconstructionAlgorithm: BACK PROJECTION / Software: Relion / Resolution: 22 Å / Resolution method: FSC 0.143 CUT-OFF
FSC plot
(resolution estimation)

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Atomic model buiding

Output model

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