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- PDB-5y0a: Cryo-EM structure of zika virus complexed with Fab of ZKA190 at p... -

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Entry
Database: PDB / ID: 5y0a
TitleCryo-EM structure of zika virus complexed with Fab of ZKA190 at pH 8.0 and 37 celsius degree
Components
  • protein E
  • variable region of Fab ZKA190 heavy chain
  • variable region of Fab ZKA190 light chain
KeywordsVIRUS/IMMUNE SYSTEM / virus / antibody / complex / VIRUS-IMMUNE SYSTEM complex / icosahedral virus
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
Specimen sourceZika virus
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / 22 Å resolution
AuthorsWang, J.Q. / Lok, S.M.
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, J.Q. / Lok, S.M.
Validation Report
SummaryFull reportAbout validation report
DateDeposition: Jul 15, 2017 / Release: Oct 4, 2017

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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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  • Superimposition on EM map
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Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: protein E
C: protein E
B: protein E
H: variable region of Fab ZKA190 heavy chain
L: variable region of Fab ZKA190 light chain
F: variable region of Fab ZKA190 heavy chain
G: variable region of Fab ZKA190 light chain
D: variable region of Fab ZKA190 heavy chain
E: variable region of Fab ZKA190 light chain


Theoretical massNumber of molelcules
Total (without water)211,2469
Polyers211,2469
Non-polymers00
Water0
1
A: protein E
C: protein E
B: protein E
H: variable region of Fab ZKA190 heavy chain
L: variable region of Fab ZKA190 light chain
F: variable region of Fab ZKA190 heavy chain
G: variable region of Fab ZKA190 light chain
D: variable region of Fab ZKA190 heavy chain
E: variable region of Fab ZKA190 light chain
x 60


Theoretical massNumber of molelcules
Total (without water)12,674,733540
Polyers12,674,733540
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
A: protein E
C: protein E
B: protein E
H: variable region of Fab ZKA190 heavy chain
L: variable region of Fab ZKA190 light chain
F: variable region of Fab ZKA190 heavy chain
G: variable region of Fab ZKA190 light chain
D: variable region of Fab ZKA190 heavy chain
E: variable region of Fab ZKA190 light chain
x 5


  • icosahedral pentamer
  • 1.06 MDa, 45 polymers
Theoretical massNumber of molelcules
Total (without water)1,056,22845
Polyers1,056,22845
Non-polymers00
Water0
TypeNameSymmetry operationNumber
point symmetry operation5
4
A: protein E
C: protein E
B: protein E
H: variable region of Fab ZKA190 heavy chain
L: variable region of Fab ZKA190 light chain
F: variable region of Fab ZKA190 heavy chain
G: variable region of Fab ZKA190 light chain
D: variable region of Fab ZKA190 heavy chain
E: variable region of Fab ZKA190 light chain
x 6


  • icosahedral 23 hexamer
  • 1.27 MDa, 54 polymers
Theoretical massNumber of molelcules
Total (without water)1,267,47354
Polyers1,267,47354
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

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Components

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


Mass: 44069.930 Da / Num. of mol.: 3 / Source: (gene. exp.) Zika virus (strain Mr 766) / Strain: Mr 766 / Cell line (production host): C6/36 / Production host: Aedes albopictus (Asian tiger mosquito) / References: UniProt: A0A1V0E2E9, UniProt: A0A024B7W1*PLUS
#2: Protein/peptide variable region of Fab ZKA190 heavy chain / Coordinate model: Cα atoms only


Mass: 14410.010 Da / Num. of mol.: 3 / Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): EXPI293 / Production host: Homo sapiens (human)
#3: Protein/peptide variable region of Fab ZKA190 light chain / Coordinate model: Cα atoms only


Mass: 11935.241 Da / Num. of mol.: 3 / Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): EXPI293 / Production host: Homo sapiens (human)

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Experimental details

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Experiment

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

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Sample preparation

Component
IDNameTypeEntity IDParent IDSource
1zika virus complexed with Fab of a human monoclonal antibody named ZKA190COMPLEX1, 2, 30MULTIPLE SOURCES
2zika virusCOMPLEX21MULTIPLE SOURCES
3Fab ZKA190COMPLEX31MULTIPLE SOURCES
Molecular weightExperimental value: NO
Source (natural)Organism: Zika virus / Strain: Mr 766
Buffer solutionpH: 8
Buffer component
IDConc.FormulaBuffer ID
1120 nMNaCl1
212 mMTris-HCl1
31 mMEDTA1
SpecimenConc.: 1 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyMicroscope model: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm
Image recordingElectron dose: 20 e/Å2 / Film or detector model: FEI FALCON II (4k x 4k)

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Processing

EM software
IDNameCategory
1Relionparticle selection
2Leginonimage acquisition
4Ctffind3CTF correction
10Relioninitial Euler assignment
11Relionfinal Euler assignment
13Relion3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: I
3D reconstructionResolution: 22 Å / Resolution method: FSC 0.143 CUT-OFF / Number of particles: 6728 / Algorithm: BACK PROJECTION / Symmetry type: POINT
Atomic model buildingRef protocol: RIGID BODY FIT

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