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- EMDB-70338: Cryo-EM structure of modified Zika virus E protein dimer complexe... -

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Basic information

Entry
Database: EMDB / ID: EMD-70338
TitleCryo-EM structure of modified Zika virus E protein dimer complexed with a neutralizing antibody SMZAb2 Fab
Map data
Sample
  • Complex: Zika virus E protein dimer complex with a neutralizing antibody SMZAB2 Fab
    • Protein or peptide: SMZAb2 Heavy chain
    • Protein or peptide: SMZAb2 Light chain
    • Protein or peptide: Envelope protein E
Keywordsneutralizing 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 speciesZika virus / Homo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.09 Å
AuthorsGalkin A / Pozharski E
Funding support United States, 1 items
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, 2025-
Header (metadata) releaseJan 21, 2026-
Map releaseJan 21, 2026-
UpdateJan 21, 2026-
Current statusJan 21, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_70338.png

Downloads & links

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Map

FileDownload / File: emd_70338.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
0.89 Å/pix.
x 360 pix.
= 320.04 Å		0.89 Å/pix.
x 360 pix.
= 320.04 Å		0.89 Å/pix.
x 360 pix.
= 320.04 Å

Surface

Projections

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.889 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.1
Minimum - Maximum-0.52505624 - 0.68769187
Average (Standard dev.)0.00025359556 (±0.013738029)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 320.04 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_70338_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_70338_half_map_2.map
Projections & Slices
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Histogram (log scale)

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Sample components

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Entire : Zika virus E protein dimer complex with a neutralizing antibody S...

EntireName: Zika virus E protein dimer complex with a neutralizing antibody SMZAB2 Fab
Components
  • Complex: Zika virus E protein dimer complex with a neutralizing antibody SMZAB2 Fab
    • Protein or peptide: SMZAb2 Heavy chain
    • Protein or peptide: SMZAb2 Light chain
    • Protein or peptide: Envelope protein E

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Supramolecule #1: Zika virus E protein dimer complex with a neutralizing antibody S...

SupramoleculeName: Zika virus E protein dimer complex with a neutralizing antibody SMZAB2 Fab
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Zika virus

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Macromolecule #1: SMZAb2 Heavy chain

MacromoleculeName: SMZAb2 Heavy chain / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 13.566996 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
EVQLVQSGAE VKKPGSSVKV SCKAPGGTFS SYAMSWVRQA PGQGPEWVGG IVPVYGTSRY AQKFQGRGTI TADESTSTVY LELSSLRSE DTALYYCARV RYYGSGTYYG GDAFDFWGQG TMVTVSS

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Macromolecule #2: SMZAb2 Light chain

MacromoleculeName: SMZAb2 Light chain / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 11.588911 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
QTVVTQEPSF SVSPGGTVTL TCGLTSDSVS IHLYPSWYQQ TPGQAPRALI YNTNTRSSGV PDRFSGSILG NKAALTITGA QADDESVYF CVVYMGSGIW VFGGGTKLTV L

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Macromolecule #3: Envelope protein E

MacromoleculeName: Envelope protein E / type: protein_or_peptide / ID: 3 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Zika virus
Molecular weightTheoretical: 47.29734 KDa
Recombinant expressionOrganism: Drosophila melanogaster (fruit fly)
SequenceString: RSGSGEQKLI SEEDLGGGGS IRCICVSNRD FVEGMSGGTW VDVVLEHGGC VTVMAQDKPT VDIELVTTTV SNMAEVRSYC YEASISDMA SDSRCPTQGE AYLDKQSDTQ YVCKRTLVDR GWCNGCGLFG KGSLVTCAKF ACSKKMTGKS IQPENLEYRI M LSVHGSQH ...String:
RSGSGEQKLI SEEDLGGGGS IRCICVSNRD FVEGMSGGTW VDVVLEHGGC VTVMAQDKPT VDIELVTTTV SNMAEVRSYC YEASISDMA SDSRCPTQGE AYLDKQSDTQ YVCKRTLVDR GWCNGCGLFG KGSLVTCAKF ACSKKMTGKS IQPENLEYRI M LSVHGSQH SGMIVNDTGH ETDENRAKVE ITPNSPRAEA TLGGFGSLGL DCEPRTGLDF SDLYYLTMNN KHWLVHKEWF HD IPLPWHA GADTGTPHWN NKEALVEFKD AHAKRQTVVV LGSQEGAVHT ALAGALEAEM DGAKGRLSSG HLKCRLKMDK LRL KGVSYS LCTAAFTFTK IPAETLHGTV TVEVQYAGTD GPCKVPAQMA VDMQTLTPVG RLITANPVIT ESTENSKMML ELDP PFGDS YIVIGVGEKK ITHHWHRSGS GTGHHHHHH

UniProtKB: Genome polyprotein

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration0.75 mg/mL
BufferpH: 7.4
GridModel: Quantifoil R2/2 / Material: GOLD / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 285 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS GLACIOS
Alignment procedureComa free - Residual tilt: 0.5 mrad
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Digitization - Dimensions - Width: 5760 pixel / Digitization - Dimensions - Height: 4092 pixel / Number grids imaged: 2 / Number real images: 3633 / Average exposure time: 2.5 sec. / Average electron dose: 52.0 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 50.0 µm / Calibrated defocus max: 2.7 µm / Calibrated defocus min: 0.5 µm / Calibrated magnification: 56200 / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.5 µm / Nominal defocus min: 0.7000000000000001 µm / Nominal magnification: 45000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN

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Image processing

Particle selectionNumber selected: 196387
CTF correctionSoftware - Name: cryoSPARC / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

5lbv

Final reconstructionApplied symmetry - Point group: C2 (2 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 4.09 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 141948
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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