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- PDB-8vsv: Cryo-EM structure of SINV/EEEV in complex with a potently neutral... -

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Basic information

Entry
Database: PDB / ID: 8vsv
TitleCryo-EM structure of SINV/EEEV in complex with a potently neutralizing intact human antibody EEEV-373
Components
  • (IgG EEEV-373 ...) x 2
  • E2 glycoprotein
  • Spike glycoprotein E1
KeywordsVIRUS / Cryo-EM / Single particle averaging / virus neutralization / intact human antibody / quaternary epitope / intra-virion crosslink / Virus-Immune system complex.
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 speciesHomo sapiens (human)
Eastern equine encephalitis virus
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.8 Å
AuthorsBandyopadhyay, A. / Klose, T. / Kuhn, R.J.
Funding support United States, 2items
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
DepositionJan 24, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 11, 2025Provider: repository / Type: Initial release
Revision 1.0Jun 11, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Jun 11, 2025Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Jun 11, 2025Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jun 11, 2025Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jun 11, 2025Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jun 11, 2025Data content type: Mask / Part number: 1 / Data content type: Mask / Provider: repository / Type: Initial release
Revision 1.0Jun 11, 2025Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Dec 24, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
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Revision 1.1Dec 24, 2025Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Database references / Experimental summary / Data content type: EM metadata / EM metadata / EM metadata / Category: citation / citation_author / em_admin
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
1: IgG EEEV-373 Heavy chain
2: IgG EEEV-373 Light chain.
3: IgG EEEV-373 Heavy chain
4: IgG EEEV-373 Light chain.
A: Spike glycoprotein E1
B: Spike glycoprotein E1
C: Spike glycoprotein E1
D: Spike glycoprotein E1
E: Spike glycoprotein E1
F: Spike glycoprotein E1
a: E2 glycoprotein
b: E2 glycoprotein
c: E2 glycoprotein
d: E2 glycoprotein
e: E2 glycoprotein
f: E2 glycoprotein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)589,50828
Polymers584,66116
Non-polymers4,84712
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

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Protein , 2 types, 12 molecules ABCDEFabcdef

#3: Protein
Spike glycoprotein E1 / E1 envelope glycoprotein


Mass: 43628.023 Da / Num. of mol.: 6
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Eastern equine encephalitis virus / Strain: Florida 93-939 / Production host: Mesocricetus auratus (golden hamster) / References: UniProt: Q4QXJ7
#4: Protein
E2 glycoprotein


Mass: 37921.133 Da / Num. of mol.: 6
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Eastern equine encephalitis virus / Strain: Florida 93-939 / Gene: E2 / Production host: Mesocricetus auratus (golden hamster) / References: UniProt: A9XR09

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Antibody , 2 types, 4 molecules 1324

#1: Antibody IgG EEEV-373 Heavy chain


Mass: 24386.211 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 IgG EEEV-373 Light chain.


Mass: 23296.922 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)

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Sugars , 2 types, 12 molecules

#5: Polysaccharide
beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta- ...beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 586.542 Da / Num. of mol.: 6
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/2,3,2/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5]/1-1-2/a4-b1_b4-c1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{}}}LINUCSPDB-CARE
#6: Sugar
ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Details

Has ligand of interestN
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: EEEV in complex with IgG EEEV-373 / Type: COMPLEX / Entity ID: #1-#4 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Culiseta melanura (mosquito)
Source (recombinant)Organism: Mesocricetus auratus (golden hamster) / Cell: BHK21
Buffer solutionpH: 7.4
SpecimenConc.: 1 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 400 divisions/in. / Grid type: EMS Lacey Carbon
VitrificationCryogen name: ETHANE / Humidity: 90 % / Chamber temperature: 298 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 3000 nm / Nominal defocus min: 1000 nm / Cs: 2.7 mm / C2 aperture diameter: 100 µm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 35.49 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)
EM imaging opticsEnergyfilter name: GIF Bioquantum / Energyfilter slit width: 20 eV

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Processing

EM software
IDNameVersionCategory
1cryoSPARCparticle selection
2Leginon3.2image acquisition
4jsprCTF correction
10jsprinitial Euler assignment
11Scipionfinal Euler assignment
12Scipionclassification
13Scipion3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 17830
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 271460 / Symmetry type: POINT
Atomic model buildingProtocol: OTHER

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