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- PDB-9od2: Cryo-EM structure of modified Zika virus E protein dimer complexe... -

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Basic information

Entry
Database: PDB / ID: 9od2
TitleCryo-EM structure of modified Zika virus E protein dimer complexed with a neutralizing antibody SMZAb2 Fab
Components
  • Envelope protein E
  • SMZAb2 Heavy chain
  • SMZAb2 Light chain
KeywordsVIRAL PROTEIN/IMMUNE SYSTEM / neutralizing antibody / VIRAL PROTEIN / VIRAL PROTEIN-Immune System complex
Function / homology
Function and homology information


flavivirin / symbiont-mediated suppression of host JAK-STAT cascade via inhibition of host TYK2 activity / 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 / double-stranded RNA binding / nucleoside-triphosphate phosphatase / 4 iron, 4 sulfur cluster binding / clathrin-dependent endocytosis of virus by host cell ...flavivirin / symbiont-mediated suppression of host JAK-STAT cascade via inhibition of host TYK2 activity / 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 / double-stranded RNA binding / nucleoside-triphosphate phosphatase / 4 iron, 4 sulfur cluster binding / clathrin-dependent endocytosis of virus by host cell / mRNA (guanine-N7)-methyltransferase / methyltransferase cap1 / molecular adaptor activity / methyltransferase cap1 activity / mRNA 5'-cap (guanine-N7-)-methyltransferase activity / RNA helicase activity / protein dimerization activity / host cell perinuclear region of cytoplasm / host cell endoplasmic reticulum membrane / RNA helicase / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / symbiont-mediated activation of host autophagy / serine-type endopeptidase activity / RNA-directed RNA polymerase / viral RNA genome replication / RNA-directed RNA polymerase activity / fusion of virus membrane with host endosome membrane / viral envelope / centrosome / lipid binding / GTP binding / virion attachment to host cell / host cell nucleus / virion membrane / structural molecule activity / ATP hydrolysis activity / proteolysis / extracellular region / ATP binding / metal ion binding / membrane
Similarity search - Function
Flavivirus capsid protein C superfamily / Flavivirus non-structural protein NS2B / Genome polyprotein, Flavivirus / : / Flavivirus non-structural protein NS4A / Flavivirus non-structural protein NS2B / Flavivirus non-structural protein NS4B / mRNA cap 0/1 methyltransferase / Flavivirus non-structural protein NS4B / Flavivirus non-structural protein NS4A ...Flavivirus capsid protein C superfamily / Flavivirus non-structural protein NS2B / Genome polyprotein, Flavivirus / : / Flavivirus non-structural protein NS4A / Flavivirus non-structural protein NS2B / Flavivirus non-structural protein NS4B / mRNA cap 0/1 methyltransferase / 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. / RNA-directed RNA polymerase, thumb domain, Flavivirus / Flavivirus RNA-directed RNA polymerase, thumb domain / RNA-directed RNA polymerase, flavivirus / Flavivirus RNA-directed RNA polymerase, fingers and palm domains / Flavivirus capsid protein C / Flavivirus capsid protein C / Flavivirus non-structural Protein NS1 / Flavivirus non-structural protein NS1 / Envelope glycoprotein M superfamily, flavivirus / Envelope glycoprotein M, flavivirus / Flavivirus polyprotein propeptide superfamily / Flavivirus envelope glycoprotein M / Flavivirus polyprotein propeptide / Flavivirus polyprotein propeptide / Flavivirus envelope glycoprotein E, Stem/Anchor domain superfamily / Flavivirus envelope glycoprotein E, stem/anchor domain / : / Flavivirus NS3 helicase, C-terminal helical domain / Flavivirus envelope glycoprotein E, Stem/Anchor domain / Flaviviral glycoprotein E, central domain, subdomain 1 / Flaviviral glycoprotein E, central domain, subdomain 2 / Flavivirus glycoprotein E, immunoglobulin-like domain / 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
Biological speciesHomo sapiens (human)
Zika virus
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.09 Å
AuthorsGalkin, A. / Pozharski, E.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID) United States
CitationJournal: Nat Commun / Year: 2025
Title: Rational design of flavivirus E protein vaccine optimizes immunogenicity and mitigates antibody dependent enhancement risk.
Authors: Yimeng Wang / Andrey Galkin / Xiaoran Shang / Alexander Marin / Shaohua Jin / Ting-Juan Ye / Shridhar Bale / Chi-I Chiang / Ananda Chowdhury / Agnes L Chenine / Ashley Turonis / Jack ...Authors: Yimeng Wang / Andrey Galkin / Xiaoran Shang / Alexander Marin / Shaohua Jin / Ting-Juan Ye / Shridhar Bale / Chi-I Chiang / Ananda Chowdhury / Agnes L Chenine / Ashley Turonis / Jack Greenhouse / Rebecca Stone / Jaclyn Wear / Swagata Kar / Hanne Andersen / Yan-Jang S Huang / Dana L Vanlandingham / Stephen Higgs / Rena G Lapidus / Thomas Fuerst / David J Weber / Richard T Wyatt / Christel Iffland / Theodore C Pierson / Alexander K Andrianov / Edwin Pozharski / Yuxing Li /
Abstract: Flaviviruses are a family of related viruses that cause substantial global morbidity and mortality. Vaccination against one flavivirus can sometimes exacerbate disease caused by related viruses ...Flaviviruses are a family of related viruses that cause substantial global morbidity and mortality. Vaccination against one flavivirus can sometimes exacerbate disease caused by related viruses through antibody-dependent enhancement (ADE) or interfere with the efficacy of subsequent vaccines. To address this challenge, we develop a vaccine strategy by introducing G5C/G102C mutations into the flavivirus envelope (E) glycoprotein. These mutations promote E dimerization through the formation of an inter-chain disulfide bond that conceals the immunodominant and ADE-prone fusion loop epitope (FLE). We validate this design on E proteins from multiple flaviviruses through biochemical, antigenic, and structural analyses. The resulting vaccine candidate, CC_FLE sE, derived from the Zika virus (ZIKV) and formulated with an advanced supramolecular adjuvant, provides significant protection in female mice challenged with ZIKV and prevents ADE caused by a related flavivirus, Dengue virus. In genetically modified mice expressing diverse human immunoglobulin loci, ZIKV CC_FLE sE induces robust neutralizing antibody responses targeting key ZIKV E protein epitopes, including the E-dimer-dependent epitope (EDE), indicating that ZIKV CC_FLE sE can elicit protective antibody responses within the human naïve B cell repertoire. Therefore, CC_FLE sE represents a promising strategy for developing flavivirus vaccines that minimize ADE risk while maintaining high protective efficacy.
History
DepositionApr 25, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 21, 2026Provider: repository / Type: Initial release
Revision 1.0Jan 21, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Jan 21, 2026Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Jan 21, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jan 21, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jan 21, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jan 21, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
C: SMZAb2 Heavy chain
D: SMZAb2 Light chain
H: SMZAb2 Heavy chain
L: SMZAb2 Light chain
A: Envelope protein E
B: Envelope protein E


Theoretical massNumber of molelcules
Total (without water)144,9066
Polymers144,9066
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein SMZAb2 Heavy chain


Mass: 13566.996 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 SMZAb2 Light chain


Mass: 11588.911 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 E


Mass: 47297.340 Da / Num. of mol.: 2 / Mutation: G5C, G102C
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Zika virus / Production host: Drosophila melanogaster (fruit fly) / References: UniProt: A0A024B7W1
Has protein modificationY

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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 E protein dimer complex with a neutralizing antibody SMZAB2 Fab
Type: COMPLEX / Entity ID: all / Source: MULTIPLE SOURCES
Source (natural)Organism: Zika virus
Source (recombinant)Organism: Drosophila (fruit flies)
Buffer solutionpH: 7.4
SpecimenConc.: 0.75 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R2/2
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 285 K

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Electron microscopy imaging

MicroscopyModel: TFS GLACIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 45000 X / Calibrated magnification: 56200 X / Nominal defocus max: 2500 nm / Nominal defocus min: 700 nm / Calibrated defocus min: 500 nm / Calibrated defocus max: 2700 nm / Cs: 2.7 mm / C2 aperture diameter: 50 µm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Residual tilt: 0.5 mradians
Image recordingAverage exposure time: 2.5 sec. / Electron dose: 52 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of grids imaged: 2 / Num. of real images: 3633
Image scansWidth: 5760 / Height: 4092

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Processing

EM software
IDNameVersionCategory
1cryoSPARCparticle selection
2SerialEM4.0.3image acquisition
4cryoSPARCCTF correction
12cryoSPARCclassification
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 196387
SymmetryPoint symmetry: C2 (2 fold cyclic)
3D reconstructionResolution: 4.09 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 141948 / Symmetry type: POINT

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