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- EMDB-43980: Cryo-EM structure of SINV/EEEV in complex with a potently neutral... -

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Basic information

Entry
Database: EMDB / ID: EMD-43980
TitleCryo-EM structure of SINV/EEEV in complex with a potently neutralizing human antibody IgG EEEV-373
Map data
Sample
  • Complex: EEEV in complex with IgG EEEV-373
    • Protein or peptide: IgG EEEV-373 Heavy chain
    • Protein or peptide: IgG EEEV-373 Light chain
    • Protein or peptide: Spike glycoprotein E1
    • Protein or peptide: E2 glycoprotein
  • Ligand: beta-D-mannopyranose
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
Keywordscryo-EM / single particle / virus neutralization / intra-virion crosslink / VIRUS-IMMUNE SYSTEM complex / VIRUS
Function / homology
Function and homology information


togavirin / T=4 icosahedral viral capsid / symbiont-mediated suppression of host toll-like receptor signaling pathway / host cell cytoplasm / symbiont-mediated suppression of host gene expression / serine-type endopeptidase activity / fusion of virus membrane with host endosome membrane / symbiont entry into host cell / virion attachment to host cell / host cell nucleus ...togavirin / T=4 icosahedral viral capsid / symbiont-mediated suppression of host toll-like receptor signaling pathway / host cell cytoplasm / symbiont-mediated suppression of host gene expression / serine-type endopeptidase activity / fusion of virus membrane with host endosome membrane / symbiont entry into host cell / virion attachment to host cell / host cell nucleus / host cell plasma membrane / virion membrane / structural molecule activity / proteolysis / RNA binding / membrane
Similarity search - Function
Alphavirus E2 glycoprotein, domain B / Peptidase S3, togavirin / Alphavirus E2 glycoprotein / Alphavirus E3 spike glycoprotein / Alphavirus E1 glycoprotein / Alphavirus E2 glycoprotein, domain A / Alphavirus E2 glycoprotein, domain C / Alphavirus E2 glycoprotein / Alphavirus core protein / Alphavirus E3 glycoprotein ...Alphavirus E2 glycoprotein, domain B / Peptidase S3, togavirin / Alphavirus E2 glycoprotein / Alphavirus E3 spike glycoprotein / Alphavirus E1 glycoprotein / Alphavirus E2 glycoprotein, domain A / Alphavirus E2 glycoprotein, domain C / Alphavirus E2 glycoprotein / Alphavirus core protein / Alphavirus E3 glycoprotein / Alphavirus E1 glycoprotein / Alphavirus core protein (CP) domain profile. / Flavivirus/Alphavirus glycoprotein, immunoglobulin-like domain superfamily / Flavivirus glycoprotein, central and dimerisation domain superfamily / Flaviviral glycoprotein E, dimerisation domain / Immunoglobulin E-set / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan
Similarity search - Domain/homology
E2 glycoprotein / Structural polyprotein
Similarity search - Component
Biological speciesEastern equine encephalitis virus / Homo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.6 Å
AuthorsBandyopadhyay A / Klose T / Kuhn RJ
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)U19 AI142790 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R01 AI095366 United States
CitationJournal: Nat Commun / Year: 2025
Title: Structural elucidation of a unique binding mode by an intact alphavirus human IgG molecule to a quaternary epitope.
Authors: Abhishek Bandyopadhyay / Lauren E Williamson / Devika Sirohi / Kevin Bailey / Theron Gilliland / Thomas Klose / Geeta Buda / Andrew Trivette / Chengqun Sun / Justin G Julander / William B ...Authors: Abhishek Bandyopadhyay / Lauren E Williamson / Devika Sirohi / Kevin Bailey / Theron Gilliland / Thomas Klose / Geeta Buda / Andrew Trivette / Chengqun Sun / Justin G Julander / William B Klimstra / James E Crowe / Richard J Kuhn /
Abstract: Eastern equine encephalitis virus (EEEV) is a mosquito-transmitted alphavirus that can cause severe encephalitis in humans and horses with a high case fatality rate. There are no licensed EEEV ...Eastern equine encephalitis virus (EEEV) is a mosquito-transmitted alphavirus that can cause severe encephalitis in humans and horses with a high case fatality rate. There are no licensed EEEV vaccines or therapeutics for human use, warranting the need to better understand the human immune response against EEEV. Here we present a cryo-EM reconstruction of the chimeric virus, Sindbis (SINV)/EEEV, in complex with a potently neutralizing and efficacious intact human IgG1 antibody in a mouse model of infection and disease. This antibody requires bivalency to recognize a quaternary epitope on the E2 glycoprotein and cross-links two virus spikes across the icosahedral two-fold axis through a unique binding mode. Kinetic analysis of the binding interaction provides insights into this distinguishing feature. Mechanistically, the antibody inhibits viral entry into cells through blockade of receptor binding and early fusion events but does not block egress, thereby, exclusively targeting an epitope found on intact virions. The discovery of the quaternary epitope and unique binding mode recognized by this antibody together advance our understanding of the complexity of antibody-antigen interactions and can aid in vaccine design to elicit recognition of distinct epitopes of clinically relevant alphaviruses.
History
DepositionMar 7, 2024-
Header (metadata) releaseJun 11, 2025-
Map releaseJun 11, 2025-
UpdateDec 24, 2025-
Current statusDec 24, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_43980.png

Downloads & links

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Map

FileDownload / File: emd_43980.map.gz / Format: CCP4 / Size: 963 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.89 Å/pix.
x 632 pix.
= 1193.216 Å		1.89 Å/pix.
x 632 pix.
= 1193.216 Å		1.89 Å/pix.
x 632 pix.
= 1193.216 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.888 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 7.0
Minimum - Maximum-24.838418999999998 - 38.561503999999999
Average (Standard dev.)0.16359131 (±2.7318692)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin-316-316-316
Dimensions632632632
Spacing632632632
CellA=B=C: 1193.2161 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_43980_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_43980_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : EEEV in complex with IgG EEEV-373

EntireName: EEEV in complex with IgG EEEV-373
Components
  • Complex: EEEV in complex with IgG EEEV-373
    • Protein or peptide: IgG EEEV-373 Heavy chain
    • Protein or peptide: IgG EEEV-373 Light chain
    • Protein or peptide: Spike glycoprotein E1
    • Protein or peptide: E2 glycoprotein
  • Ligand: beta-D-mannopyranose
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: EEEV in complex with IgG EEEV-373

SupramoleculeName: EEEV in complex with IgG EEEV-373 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4
Source (natural)Organism: Eastern equine encephalitis virus / Strain: FL93-939

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Macromolecule #1: IgG EEEV-373 Heavy chain

MacromoleculeName: IgG EEEV-373 Heavy chain / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 24.386211 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: QVQLVESGGG VVQPGRSLRL SCAASGFTFS SHVMYWVRQA PGKGLEWVAV ITYDGGNKYY ADSVRGRLTI SRDNSKNTLY LQMNSLRAE DTAVYYCASP RGDSGSYYDI DYFDYWGQGT LVTVSSASTK GPSVFPLAPS SKSTSGGTAA LGCLVKDYFP E PVTVSWNS ...String:
QVQLVESGGG VVQPGRSLRL SCAASGFTFS SHVMYWVRQA PGKGLEWVAV ITYDGGNKYY ADSVRGRLTI SRDNSKNTLY LQMNSLRAE DTAVYYCASP RGDSGSYYDI DYFDYWGQGT LVTVSSASTK GPSVFPLAPS SKSTSGGTAA LGCLVKDYFP E PVTVSWNS GALTSGVHTF PAVLQSSGLY SLSSVVTVPS SSLGTQTYIC NVNHKPSNTK VDKKVEPKSC

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Macromolecule #2: IgG EEEV-373 Light chain

MacromoleculeName: IgG EEEV-373 Light chain / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.296922 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: DIQMTQSPSA MSASVGDRVT ITCRASQGIS NYLAWFQQKP GKVPKRLIYA ASSLQSGVPS RFSGSGSGTE FTLTISSLQP EDFATYYCL QHNTSPSPFG QGTKVEIKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF YPREAKVQWK VDNALQSGNS Q ESVTEQDS ...String:
DIQMTQSPSA MSASVGDRVT ITCRASQGIS NYLAWFQQKP GKVPKRLIYA ASSLQSGVPS RFSGSGSGTE FTLTISSLQP EDFATYYCL QHNTSPSPFG QGTKVEIKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF YPREAKVQWK VDNALQSGNS Q ESVTEQDS KDSTYSLSST LTLSKADYEK HKLYACEVTH QGLSSPVTKS FNRGEC

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Macromolecule #3: Spike glycoprotein E1

MacromoleculeName: Spike glycoprotein E1 / type: protein_or_peptide / ID: 3 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Eastern equine encephalitis virus / Strain: FL 93-939
Molecular weightTheoretical: 43.628023 KDa
Recombinant expressionOrganism: Mesocricetus auratus (golden hamster)
SequenceString: YEHTAVMPNK VGIPYKALVE RPGYAPVHLQ IQLVNTRIIP STNLEYITCK YKTKVPSPVV KCCGATQCTS KPHPDYQCQV FTGVYPFMW GGAYCFCDTE NTQMSEAYVE RSEECSIDHA KAYKVHTGTV QAMVNITYGS VSWRSADVYV NGETPAKIGD A KLIIGPLS ...String:
YEHTAVMPNK VGIPYKALVE RPGYAPVHLQ IQLVNTRIIP STNLEYITCK YKTKVPSPVV KCCGATQCTS KPHPDYQCQV FTGVYPFMW GGAYCFCDTE NTQMSEAYVE RSEECSIDHA KAYKVHTGTV QAMVNITYGS VSWRSADVYV NGETPAKIGD A KLIIGPLS SAWSPFDNKV VVYGHEVYNY DFPEYGTGKA GSFGDLQSRT STSNDLYANT NLKLQRPQAG IVHTPFTQAP SG FERWKRD KGAPLNDVAP FGCSIALEPL RAENCAVGSI PISIDIPDAA FTRISETPTV SDLECKITEC TYASDFGGIA TVA YKSSKA GNCPIHSPSG VAVIKENDVT LAESGSFTFH FSTANIHPAF KLQVCTSAVT CKGDCKPPKD HIVDYPAQHT ESFT

UniProtKB: Structural polyprotein

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Macromolecule #4: E2 glycoprotein

MacromoleculeName: E2 glycoprotein / type: protein_or_peptide / ID: 4 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Eastern equine encephalitis virus / Strain: FL 93-939
Molecular weightTheoretical: 37.921133 KDa
Recombinant expressionOrganism: Mesocricetus auratus (golden hamster)
SequenceString: DLDTHFTQYK LARPYIADCP NCGHSRCDSP IAIEEVRGDA HAGVIRIQTS AMFGLKTDGV DLAYMSFMNG KTQKSIKIDN LHVRTSAPC SLVSHHGYYI LAQCPPGDTV TVGFHDGPNR HTCTVAHKVE FRPVGREKYR HPPEHGVELP CNRYTHKRAD Q GHYVEMHQ ...String:
DLDTHFTQYK LARPYIADCP NCGHSRCDSP IAIEEVRGDA HAGVIRIQTS AMFGLKTDGV DLAYMSFMNG KTQKSIKIDN LHVRTSAPC SLVSHHGYYI LAQCPPGDTV TVGFHDGPNR HTCTVAHKVE FRPVGREKYR HPPEHGVELP CNRYTHKRAD Q GHYVEMHQ PGLVADHSLL SIHSAKVKIT VPSGAQVKYY CKCPDVREGI TSSDHTTTCT DVKQCRAYLI DNKKWVYNSG RL PRGEGDT FKGKLHVPFV PVKAKCIATL APEPLVEHKH RTLILHLHPD HPTLLTTRSL GSDANPTRQW IERPTTVNFT VTG EGLEYT WGNHPPKRVW AQ

UniProtKB: E2 glycoprotein

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Macromolecule #7: beta-D-mannopyranose

MacromoleculeName: beta-D-mannopyranose / type: ligand / ID: 7 / Number of copies: 1 / Formula: BMA
Molecular weightTheoretical: 180.156 Da
Chemical component information

ChemComp-BMA:
beta-D-mannopyranose

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Macromolecule #8: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 8 / Number of copies: 4 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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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

Concentration1 mg/mL
BufferpH: 7.4
GridModel: EMS Lacey Carbon / Material: COPPER / Mesh: 400 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 60 sec.
VitrificationCryogen name: ETHANE / Chamber humidity: 80 % / Chamber temperature: 298 K

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Specialist opticsEnergy filter - Name: GIF Bioquantum / Energy filter - Slit width: 20 eV
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 35.49 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 100.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 3.0 µm / Nominal defocus min: 1.0 µm
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 17830
CTF correctionSoftware - Name: cryoSPARC / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: OTHER
Final reconstructionNumber classes used: 1 / Applied symmetry - Point group: I (icosahedral) / Resolution.type: BY AUTHOR / Resolution: 4.6 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: jspr / Number images used: 15932
Initial angle assignmentType: RANDOM ASSIGNMENT / Software - Name: jspr
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: jspr
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

6mx4


Chain - Source name: PDB / Chain - Initial model type: experimental model
RefinementProtocol: RIGID BODY FIT
Output model

PDB-9ay1:
Cryo-EM structure of SINV/EEEV in complex with a potently neutralizing human antibody IgG EEEV-373

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