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- PDB-9z5u: Cryo-EM structure of a soluble HCV E1E2 antigen in complex with A... -

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Basic information

Entry
Database: PDB / ID: 9z5u
TitleCryo-EM structure of a soluble HCV E1E2 antigen in complex with AT1211 fab
Components
  • AT1211 Heavy Chain
  • AT1211 Light Chain
  • sE1E2
KeywordsVIRAL PROTEIN / Hepatitis C / broadly neutralizing antibody / soluble antigen
Biological speciesHepacivirus hominis
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.06 Å
AuthorsCannac, F. / Ward, A.B.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Nat Commun / Year: 2026
Title: Structure-based design of stable recombinant hepatitis C virus E1E2 heterodimers.
Authors: Joan Capella-Pujol / Fabian Mulder / Fabien Cannac / Stan Peters / Maddy L Newby / Meliawati Poniman / Ian Zon / Wouter Olijhoek / Tim Beaumont / Max Crispin / Andrew B Ward / Janke Schinkel ...Authors: Joan Capella-Pujol / Fabian Mulder / Fabien Cannac / Stan Peters / Maddy L Newby / Meliawati Poniman / Ian Zon / Wouter Olijhoek / Tim Beaumont / Max Crispin / Andrew B Ward / Janke Schinkel / Rogier W Sanders / Kwinten Sliepen /
Abstract: Hepatitis C virus (HCV) affects 47 million people and causes 239,000 deaths annually, yet no vaccine is on the horizon. Generating a stable native-like mimic of the envelope complex E1E2, the only ...Hepatitis C virus (HCV) affects 47 million people and causes 239,000 deaths annually, yet no vaccine is on the horizon. Generating a stable native-like mimic of the envelope complex E1E2, the only target for known neutralizing antibodies, is an important aim for HCV vaccine development. Starting from a recombinant E1E2 design that utilizes a leucine zipper for proper folding, we used an iterative structure-based design approach to engineer antigens with at least 100-fold stronger binding to conformational antibodies and increased thermal stability. These new E1E2 designs facilitate production of native-like E1E2 antigens based on strains from different HCV genotypes and enable the generation of a recombinant E1E2 antigen design that lacks the immunogenic leucine zipper. A cryo-EM structure of one of the stabilized E1E2 antigens in complex with neutralizing antibody AT1211 provides atomic-level insights into an atypical epitope on the E2 subunit. Finally, immunogenicity studies in rabbits with adjuvanted E1E2 proteins show that immunogen stabilization alone does do not enhance serum neutralization breadth, but that removing the leucine zipper does increase homologous serum neutralization.
History
DepositionNov 12, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 1, 2026Provider: repository / Type: Initial release
Revision 1.0Jul 1, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Jul 1, 2026Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Jul 1, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
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Revision 1.0Jul 1, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jul 1, 2026Data content type: Mask / Part number: 1 / Data content type: Mask / Provider: repository / Type: Initial release
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Revision 1.1Sep 9, 2026Group: Data collection / Database references / Category: citation / citation_author / em_admin
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Revision 1.1Sep 9, 2026Data 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
A: sE1E2
H: AT1211 Heavy Chain
L: AT1211 Light Chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)113,9587
Polymers112,5043
Non-polymers1,4534
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein , 1 types, 1 molecules A

#1: Protein sE1E2


Mass: 64587.008 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Hepacivirus hominis / Production host: Homo sapiens (human)

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Antibody , 2 types, 2 molecules HL

#2: Antibody AT1211 Heavy Chain


Mass: 24437.383 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#3: Antibody AT1211 Light Chain


Mass: 23480.043 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)

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Sugars , 3 types, 4 molecules

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


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}LINUCSPDB-CARE
#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.: 1
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.: 2 / 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: Cryo-EM structure of a soluble HCV E1E2 antigen in complex with AT1211 fab
Type: COMPLEX / Entity ID: #1-#3 / Source: MULTIPLE SOURCES
Molecular weightExperimental value: NO
Source (natural)Organism: Hepacivirus hominis
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 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: 190000 X / Nominal defocus max: 1600 nm / Nominal defocus min: 600 nm / Cs: 2.7 mm / C2 aperture diameter: 20 µm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingAverage exposure time: 6.2 sec. / Electron dose: 60 e/Å2 / Film or detector model: TFS FALCON 4i (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 1827

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Processing

EM software
IDNameVersionCategory
1cryoSPARCparticle selection
2PHENIX1.21.1_5286model refinement
5cryoSPARCCTF correction
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.06 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 164770 / Symmetry type: POINT
RefinementHighest resolution: 3.06 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0053448
ELECTRON MICROSCOPYf_angle_d0.9344701
ELECTRON MICROSCOPYf_dihedral_angle_d11.0671330
ELECTRON MICROSCOPYf_chiral_restr0.052518
ELECTRON MICROSCOPYf_plane_restr0.007595

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