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- PDB-5omz: Solution structure of domain III (DIII)of Zika virus Envelope protein -

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Entry
Database: PDB / ID: 5omz
TitleSolution structure of domain III (DIII)of Zika virus Envelope protein
ComponentsEnvelope ProteinViral envelope
KeywordsVIRAL PROTEIN / ZIKA virus Envelope protein domain / ZIKV
Function / homologyDEAD box, Flavivirus / Helicase superfamily 1/2, ATP-binding domain / Flavivirus non-structural protein NS4B / 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 / Peptidase S7, Flavivirus NS3 serine protease ...DEAD box, Flavivirus / Helicase superfamily 1/2, ATP-binding domain / Flavivirus non-structural protein NS4B / 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 / Peptidase S7, Flavivirus NS3 serine protease / Flavivirus glycoprotein central and dimerisation domain / Flaviviral glycoprotein E, central domain, subdomain 1 / Flaviviral glycoprotein E, central domain, subdomain 2 / Genome polyprotein, Flavivirus / Flavivirus capsid protein C / Immunoglobulin E-set / Flavivirus envelope glycoprotein E, Stem/Anchor domain / mRNA cap 0/1 methyltransferase / Flavivirus glycoprotein E, immunoglobulin-like domain / P-loop containing nucleoside triphosphate hydrolase / S-adenosyl-L-methionine-dependent methyltransferase / Flavivirus glycoprotein, central and dimerisation domain superfamily / Flavivirus capsid protein C superfamily / Flaviviral glycoprotein E, dimerisation domain / Envelope glycoprotein M superfamily, flavivirus / Flavivirus envelope glycoprotein E, Stem/Anchor domain superfamily / Flavivirus polyprotein propeptide superfamily / Flavivirus non-structural protein NS1 / Flavivirus non-structural protein NS2A / Flavivirus non-structural Protein NS1 / Flavivirus non-structural protein NS2B / 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 / Envelope glycoprotein M, flavivirus / RNA-directed RNA polymerase, flavivirus / Flavivirus/Alphavirus glycoprotein, immunoglobulin-like domain superfamily / Flavivirus non-structural protein NS4A / Flavivirus glycoprotein, central and dimerisation domains / suppression by virus of host STAT2 activity / mRNA (nucleoside-2'-O-)-methyltransferase activity / mRNA (guanine-N7-)-methyltransferase activity / host cell endoplasmic reticulum membrane / ATP-dependent helicase activity / RNA helicase activity / double-stranded RNA binding / suppression by virus of host type I interferon-mediated signaling pathway / viral capsid / induction by virus of host autophagy / 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 / virion membrane / structural molecule activity / serine-type endopeptidase activity / integral component of membrane / extracellular region / ATP binding / metal ion binding / Genome polyprotein / Genome polyprotein
Function and homology information
Specimen sourceZika virus
MethodSOLUTION NMR / simulated annealing
AuthorsZerbe, O. / Bardelli, M.
CitationJournal: 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.
Validation Report
SummaryFull reportAbout validation report
DateDeposition: Aug 2, 2017 / Release: Oct 4, 2017

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Structure visualization

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Assembly

Deposited unit
A: Envelope Protein


Theoretical massNumber of molelcules
Total (without water)12,4791
Polyers12,4791
Non-polymers00
Water0
1


  • idetical with deposited unit
  • defined by author&software
  • Evidence: light scattering, gel filtration
  • Download structure data
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area (Å2)0
ΔGint (kcal/M)0
Surface area (Å2)9230
MethodPISA
NMR ensembles
Datacriteria
Number of conformers (submitted / calculated)20 / 100structures with the lowest energy
RepresentativeModel #1lowest energy

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Components

#1: Protein/peptide Envelope Protein / Viral envelope


Mass: 12479.393 Da / Num. of mol.: 1 / Fragment: DOMAIN DIII, UNP residues 585-699 / Source: (gene. exp.) Zika virus (strain Mr 766) / Plasmid name: pET21a / Production host: Escherichia coli (E. coli) / References: UniProt: A0A1V0E2E5, UniProt: A0A0X8GJ44*PLUS

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Experimental details

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Experiment

ExperimentMethod: SOLUTION NMR
NMR experiment
Conditions IDExperiment IDSolution IDSample stateSpectrometer IDType
111isotropic12D 1H-15N HSQC
1151isotropic22D 1H-13C HSQC aliphatic
1161isotropic22D 1H-13C HSQC aromatic
151isotropic23D HNCO
1101isotropic23D HN(CA)CO
131isotropic23D CBCA(CO)NH
141isotropic23D HNCACB
1121isotropic23D HCCH-TOCSY
1141isotropic23D H(C)CH
1111isotropic23D HBHA(CO)NH
191isotropic23D 1H-15N NOESY
181isotropic23D 1H-13C NOESY aliphatic
171isotropic23D 1H-13C NOESY aromatic
122isotropic22D 1H-15N HSQC
162isotropic23D 1H-15N NOESY
1132isotropic23D HNCO

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Sample preparation

Details
TypeSolution IDContentsDetailsLabelSolvent system
solution1800 uM 15N,13C ZIKA Envelope DIII, 20 mM sodium phosphate, 50 mM sodium chloride, 90% H2O/10% D2Osample for resonance assignment and structure determinationsample_H2O90% H2O/10% D2O
solution2400 uM 2H,13C,15N ZIKA Envelope DIII, 20 mM sodium phosphate, 50 mM sodium chloride, 440 uM ZKA190 Fab, 90% H2O/10% D2Operdeuterated 13C,15N samplesample for mapping90% H2O/10% D2O
Sample
Conc.ComponentIsotopic labelingSolution ID
800 uMZIKA Envelope DIII15N,13C1
20 mMsodium phosphatenatural abundance1
50 mMsodium chloridenatural abundance1
400 uMZIKA Envelope DIII2H,13C,15N2
20 mMsodium phosphatenatural abundance2
50 mMsodium chloridenatural abundance2
440 uMZKA190 Fabnatural abundance2
sample conditionsIonic strength: 0.27 mM / Label: conditions_1 / pH: 6.0 / Pressure: 1 atm / Temperature: 300 K

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NMR measurement

NMR spectrometer
TypeManufacturerModelField strengthSpectrometer ID
Bruker AV-4BrukerAV-46001
Bruker AvanceBrukerAvance7002

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Processing

NMR software
NameVersionDeveloperClassification
TOPSPIN2.1Bruker Biospinprocessing
CARA1.93Keller and Wuthrichchemical shift assignment
CYANA3.97Guntert, Mumenthaler and Wuthrichstructure calculation
RefinementMethod: simulated annealing / Software ordinal: 5 / Details: further refinement in AMBER
NMR representativeSelection criteria: lowest energy
NMR ensembleConformer selection criteria: structures with the lowest energy
Conformers calculated total number: 100 / Conformers submitted total number: 20

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