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- EMDB-41247: CryoEM structure of neutralizing antibody HC84.26 in complex with... -

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Basic information

Entry
Database: EMDB / ID: EMD-41247
TitleCryoEM structure of neutralizing antibody HC84.26 in complex with Hepatitis C virus envelope glycoprotein E2
Map data
Sample
  • Complex: HCV E2-HC84.26 complex
    • Protein or peptide: envelope glycoprotein E2
    • Protein or peptide: HC84.26 Heavy chain
    • Protein or peptide: HC84.26 Light chain
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
KeywordsHCV / E2 / Fab / antiviral / complex / ANTIVIRAL PROTEIN
Function / homology
Function and homology information


host cell lipid droplet / clathrin-dependent endocytosis of virus by host cell / host cell endoplasmic reticulum membrane / fusion of virus membrane with host endosome membrane / viral envelope / virion attachment to host cell / virion membrane
Similarity search - Function
Hepatitis C virus, Non-structural protein E2/NS1 / Hepatitis C virus non-structural protein E2/NS1 / Hepatitis C virus, Envelope glycoprotein E1 / Hepatitis C virus envelope glycoprotein E1
Similarity search - Domain/homology
Biological speciesHomo sapiens (human) / Hepacivirus C
Methodsingle particle reconstruction / cryo EM / Resolution: 3.78 Å
AuthorsShahid S / Liqun J / Liu Y / Hasan SS / Mariuzza RA
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R01 AI168048 United States
CitationJournal: Commun Biol / Year: 2025
Title: Cryo-EM structures of HCV E2 glycoprotein bound to neutralizing and non-neutralizing antibodies determined using bivalent Fabs as fiducial markers.
Authors: Salman Shahid / Sharanbasappa S Karade / S Saif Hasan / Rui Yin / Liqun Jiang / Yanxin Liu / Nathaniel Felbinger / Liudmila Kulakova / Eric A Toth / Zhen-Yong Keck / Steven K H Foung / ...Authors: Salman Shahid / Sharanbasappa S Karade / S Saif Hasan / Rui Yin / Liqun Jiang / Yanxin Liu / Nathaniel Felbinger / Liudmila Kulakova / Eric A Toth / Zhen-Yong Keck / Steven K H Foung / Thomas R Fuerst / Brian G Pierce / Roy A Mariuzza /
Abstract: Global elimination of hepatitis C virus (HCV) will require an effective cross-genotype vaccine. The HCV E2 envelope glycoprotein is the main target of neutralizing antibodies but also contains ...Global elimination of hepatitis C virus (HCV) will require an effective cross-genotype vaccine. The HCV E2 envelope glycoprotein is the main target of neutralizing antibodies but also contains epitopes that elicit non-neutralizing antibodies which may provide protection through Fc effector functions rather than direct neutralization. We determined cryo-EM structures of a broadly neutralizing antibody, a moderately neutralizing antibody, and a non-neutralizing antibody bound to E2 to resolutions of 3.8, 3.3, and 3.7 Å, respectively. Whereas the broadly neutralizing antibody targeted the front layer of E2 and the non-neutralizing antibody targeted the back layer, the moderately neutralizing antibody straddled both front and back layers, and thereby defined a new neutralizing epitope on E2. The small size of complexes between conventional (monovalent) Fabs and E2 (~110 kDa) presented a challenge for cryo-EM. Accordingly, we engineered bivalent versions of E2-specific Fabs that doubled the size of Fab-E2 complexes and conferred highly identifiable shapes to the complexes that facilitated particle selection and orientation for image processing. This study validates bivalent Fabs as new fiducial markers for cryo-EM analysis of small proteins such as HCV E2 and identifies a new target epitope for vaccine development.
History
DepositionJul 13, 2023-
Header (metadata) releaseJul 24, 2024-
Map releaseJul 24, 2024-
UpdateJul 9, 2025-
Current statusJul 9, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_41247.png

Downloads & links

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Map

FileDownload / File: emd_41247.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.49 Å/pix.
x 256 pix.
= 380.8 Å		1.49 Å/pix.
x 256 pix.
= 380.8 Å		1.49 Å/pix.
x 256 pix.
= 380.8 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.4875 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.22
Minimum - Maximum-2.795557 - 3.619805
Average (Standard dev.)-0.0008756338 (±0.042297453)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 380.8 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_41247_msk_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_41247_half_map_1.map
Projections & Slices
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Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_41247_half_map_2.map
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Sample components

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Entire : HCV E2-HC84.26 complex

EntireName: HCV E2-HC84.26 complex
Components
  • Complex: HCV E2-HC84.26 complex
    • Protein or peptide: envelope glycoprotein E2
    • Protein or peptide: HC84.26 Heavy chain
    • Protein or peptide: HC84.26 Light chain
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: HCV E2-HC84.26 complex

SupramoleculeName: HCV E2-HC84.26 complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 340 KDa

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Macromolecule #1: envelope glycoprotein E2

MacromoleculeName: envelope glycoprotein E2 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Hepacivirus C
Molecular weightTheoretical: 32.28726 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: METDTLLLWV LLLWVPGSTG DSTHVTGGTA SHTTRHFASL FSSGASQRVQ LINTNGSWHI NRTALNCNDS LHTGFLAALF YTHKFNASG CPERMAHCRP IDEFAQGWGP ITYAEGHGSD QRPYCWHYAP RQCGTIPASQ VCGPVYCFTP SPVVVGTTDR F GAPTYTWG ...String:
METDTLLLWV LLLWVPGSTG DSTHVTGGTA SHTTRHFASL FSSGASQRVQ LINTNGSWHI NRTALNCNDS LHTGFLAALF YTHKFNASG CPERMAHCRP IDEFAQGWGP ITYAEGHGSD QRPYCWHYAP RQCGTIPASQ VCGPVYCFTP SPVVVGTTDR F GAPTYTWG ENETDVLILN NTRPPQGNWF GCTWMNSTGF TKTCGGPPCN IGGVGNNTLT CPTDCFRKHP EATYTKCGSG PW LTPRCLV DYPYRLWHYP CTVNFTIFKV RMYVGGVEHR LNAACNIGHH HHHH

UniProtKB: Genome polyprotein

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Macromolecule #2: HC84.26 Heavy chain

MacromoleculeName: HC84.26 Heavy chain / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 27.304617 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: METDTLLLWV LLLWVPGSTG DQVQPVQSGA EVKKPGSSVK VSCEASGGTH SNYVITWVRQ APGQGLEWMG GFIPDFRTAM YAQGFQGRV TITADESTSL AYMELTNLRS EDTAVYYCAR GPLSRGYYDY WGPGTLVTVS ASTKGPSVFP LAPSSKSTSG G TAALGCLV ...String:
METDTLLLWV LLLWVPGSTG DQVQPVQSGA EVKKPGSSVK VSCEASGGTH SNYVITWVRQ APGQGLEWMG GFIPDFRTAM YAQGFQGRV TITADESTSL AYMELTNLRS EDTAVYYCAR GPLSRGYYDY WGPGTLVTVS ASTKGPSVFP LAPSSKSTSG G TAALGCLV KDYFPEPVTV SWNSGALTSG VHTFPAVLQS SGLYSLSSVV TVPSSSLGTQ TYICNVNHKP SNTKVDKRVE PK SCDKTAG WSHPQFEK

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Macromolecule #3: HC84.26 Light chain

MacromoleculeName: HC84.26 Light chain / type: protein_or_peptide / ID: 3 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 25.35215 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: METDTLLLWV LLLWVPGSTG DSYVLTQPPS VSVAPGQTAS ITCSGDKLGD KYVSWYQQRP GQSPVLVLYQ DSKRPSGIPE RFSGSNSGN TATLTISGTQ AMDEADYYCQ AWDSSALVFG GGTKLTVLRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF Y PREAKVQW ...String:
METDTLLLWV LLLWVPGSTG DSYVLTQPPS VSVAPGQTAS ITCSGDKLGD KYVSWYQQRP GQSPVLVLYQ DSKRPSGIPE RFSGSNSGN TATLTISGTQ AMDEADYYCQ AWDSSALVFG GGTKLTVLRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF Y PREAKVQW KVDNALQSGN SQESVTEQDS KDSTYSLSST LTLSKADYEK HKVYACEVTH QGLSSPVTKS FNRGEC

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Macromolecule #7: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 7 / Number of copies: 3 / 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

Concentration0.5 mg/mL
BufferpH: 8 / Details: 20 mM Tris-HCl pH 8.0, 100 mM NaCl
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300 / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Number grids imaged: 1 / Number real images: 9653 / Average exposure time: 3.8 sec. / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 100.0 µm / Illumination mode: OTHER / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.0 µm / Nominal magnification: 81000
Sample stageCooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionSoftware - Name: cryoSPARC / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.78 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 180188
Initial angle assignmentType: OTHER
Final angle assignmentType: OTHER
Final 3D classificationNumber classes: 5
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementProtocol: AB INITIO MODEL
Output model

PDB-8tgz:
CryoEM structure of neutralizing antibody HC84.26 in complex with Hepatitis C virus envelope glycoprotein E2

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