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- EMDB-19243: HCV E1/E2 homodimer complex -

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Basic information

Entry
Database: EMDB / ID: EMD-19243
TitleHCV E1/E2 homodimer complex
Map data
Sample
  • Complex: HCV S52 E1E2
    • Protein or peptide: Genome polyprotein
    • Protein or peptide: HCV S52 E2
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
KeywordsHepatitis C virus S52 E1 E2 Homodimer Structure / VIRAL PROTEIN
Function / homology
Function and homology information


host cell mitochondrial membrane / host cell lipid droplet / symbiont-mediated transformation of host cell / symbiont-mediated suppression of host TRAF-mediated signal transduction / symbiont-mediated perturbation of host cell cycle G1/S transition checkpoint / symbiont-mediated suppression of host JAK-STAT cascade via inhibition of STAT1 activity / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of MAVS activity / ribonucleoside triphosphate phosphatase activity / channel activity / viral nucleocapsid ...host cell mitochondrial membrane / host cell lipid droplet / symbiont-mediated transformation of host cell / symbiont-mediated suppression of host TRAF-mediated signal transduction / symbiont-mediated perturbation of host cell cycle G1/S transition checkpoint / symbiont-mediated suppression of host JAK-STAT cascade via inhibition of STAT1 activity / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of MAVS activity / ribonucleoside triphosphate phosphatase activity / channel activity / viral nucleocapsid / monoatomic ion transmembrane transport / clathrin-dependent endocytosis of virus by host cell / RNA helicase activity / host cell perinuclear region of cytoplasm / host cell endoplasmic reticulum membrane / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / ribonucleoprotein complex / symbiont-mediated activation of host autophagy / serine-type endopeptidase activity / cysteine-type endopeptidase activity / viral RNA genome replication / RNA-directed RNA polymerase activity / fusion of virus membrane with host endosome membrane / viral envelope / 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 / zinc ion binding / ATP binding / membrane
Similarity search - Function
Hepatitus C virus, Non-structural 5a protein, C-terminal / Hepatitis C virus NS5A, 1B domain superfamily / Hepatitis C virus non-structural protein NS2, C-terminal domain / Hepatitis C virus non-structural protein NS2, N-terminal domain / Hepatitis C virus non-structural protein NS2 / HCV NS5a protein C-terminal region / Hepatitis C virus, Non-structural protein NS4b / Hepatitis C virus, Core protein, N-terminal / Hepatitis C virus core protein, chain A superfamily / : ...Hepatitus C virus, Non-structural 5a protein, C-terminal / Hepatitis C virus NS5A, 1B domain superfamily / Hepatitis C virus non-structural protein NS2, C-terminal domain / Hepatitis C virus non-structural protein NS2, N-terminal domain / Hepatitis C virus non-structural protein NS2 / HCV NS5a protein C-terminal region / Hepatitis C virus, Non-structural protein NS4b / Hepatitis C virus, Core protein, N-terminal / Hepatitis C virus core protein, chain A superfamily / : / Hepatitis C virus non-structural protein NS4b / Hepatitis C virus capsid protein / Hepatitis C virus, Non-structural protein NS2 / Hepatitis C virus, Non-structural 5a protein / Hepatitis C virus, Non-structural 5a protein, domain 1a / Hepatitis C virus non-structural 5a, 1B domain / NS5A domain 1a superfamily / : / Hepatitis C virus non-structural 5a protein membrane anchor / Hepatitis C virus non-structural 5a zinc finger domain / Hepatitis C virus non-structural 5a domain 1b / NS3 RNA helicase, C-terminal helical domain / Hepacivirus nonstructural protein 2 (NS2) protease domain profile. / Hepatitis C virus, Non-structural protein NS4a / Hepatitis C virus non-structural protein NS4a / Hepatitis C virus, Core protein, C-terminal / Hepatitis C virus core protein / 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 / RNA dependent RNA polymerase, hepatitis C virus / Viral RNA dependent RNA polymerase / Hepatitis C virus, NS3 protease, Peptidase S29 / Hepatitis C virus NS3 protease / Hepacivirus/Pegivirus NS3 protease domain profile. / DEAD box, Flavivirus / Flavivirus DEAD domain / 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 / Reverse transcriptase/Diguanylate cyclase domain / RNA-directed RNA polymerase, catalytic domain / RdRp of positive ssRNA viruses catalytic domain profile. / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan / DNA/RNA polymerase superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Genome polyprotein / Genome polyprotein
Similarity search - Component
Biological speciesHepacivirus hominis
Methodsingle particle reconstruction / cryo EM / Resolution: 3.55 Å
AuthorsAugestad EH / Olesen CH / Groenberg C / Soerensen A / Velazquez-Moctezuma R / Fanalista M / Bukh J / Wang K / Gourdon P / Prentoe J
Funding support Denmark, 2 items
OrganizationGrant numberCountry
LundbeckfondenR324-2019-1375 Denmark
Novo Nordisk FoundationNNF20SA0064340 Denmark
CitationJournal: Nature / Year: 2024
Title: The hepatitis C virus envelope protein complex is a dimer of heterodimers.
Authors: Elias Honerød Augestad / Christina Holmboe Olesen / Christina Grønberg / Andreas Soerensen / Rodrigo Velázquez-Moctezuma / Margherita Fanalista / Jens Bukh / Kaituo Wang / Pontus Gourdon ...Authors: Elias Honerød Augestad / Christina Holmboe Olesen / Christina Grønberg / Andreas Soerensen / Rodrigo Velázquez-Moctezuma / Margherita Fanalista / Jens Bukh / Kaituo Wang / Pontus Gourdon / Jannick Prentoe /
Abstract: Fifty-eight million individuals worldwide are affected by chronic hepatitis C virus (HCV) infection, a primary driver of liver cancer for which no vaccine is available. The HCV envelope proteins E1 ...Fifty-eight million individuals worldwide are affected by chronic hepatitis C virus (HCV) infection, a primary driver of liver cancer for which no vaccine is available. The HCV envelope proteins E1 and E2 form a heterodimer (E1/E2), which is the target for neutralizing antibodies. However, the higher-order organization of these E1/E2 heterodimers, as well as that of any Hepacivirus envelope protein complex, remains unknown. Here we determined the cryo-electron microscopy structure of two E1/E2 heterodimers in a homodimeric arrangement. We reveal how the homodimer is established at the molecular level and provide insights into neutralizing antibody evasion and membrane fusion by HCV, as orchestrated by E2 motifs such as hypervariable region 1 and antigenic site 412, as well as the organization of the transmembrane helices, including two internal to E1. This study addresses long-standing questions on the higher-order oligomeric arrangement of Hepacivirus envelope proteins and provides a critical framework in the design of novel HCV vaccine antigens.
History
DepositionDec 21, 2023-
Header (metadata) releaseSep 4, 2024-
Map releaseSep 4, 2024-
UpdateOct 23, 2024-
Current statusOct 23, 2024Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_19243.png

Downloads & links

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Map

FileDownload / File: emd_19243.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.82 Å/pix.
x 320 pix.
= 263.68 Å		0.82 Å/pix.
x 320 pix.
= 263.68 Å		0.82 Å/pix.
x 320 pix.
= 263.68 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.824 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.25
Minimum - Maximum-0.3099158 - 0.7734145
Average (Standard dev.)0.0036068538 (±0.030592952)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 263.68 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_19243_msk_1.map
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Additional map: EMready map

Fileemd_19243_additional_1.map
AnnotationEMready map
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Half map: #2

Fileemd_19243_half_map_1.map
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Half map: #1

Fileemd_19243_half_map_2.map
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Sample components

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Entire : HCV S52 E1E2

EntireName: HCV S52 E1E2
Components
  • Complex: HCV S52 E1E2
    • Protein or peptide: Genome polyprotein
    • Protein or peptide: HCV S52 E2
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: HCV S52 E1E2

SupramoleculeName: HCV S52 E1E2 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Hepacivirus hominis
Molecular weightTheoretical: 200 KDa

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Macromolecule #1: Genome polyprotein

MacromoleculeName: Genome polyprotein / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Hepacivirus hominis
Molecular weightTheoretical: 20.681846 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
EWRNTSGLYV LTNDCSNSSI VYEADDVILH TPGCVPCVQD DNTSTCWTPV TPTVAVRYVG ATTASIRSHV DLLVGAATLC SALYVGDMC GAVFLVGQAF TFRPRRHQTV QTCNCSLYPG HVSGHRMAWD MMMNWSPAVG MVVAHILRLP QTLFDILAGA H WGVLAGIA YFSMVGNWAK VLVVLLLFAG VDA

UniProtKB: Genome polyprotein

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Macromolecule #2: HCV S52 E2

MacromoleculeName: HCV S52 E2 / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Hepacivirus hominis / Strain: S52
Molecular weightTheoretical: 41.050758 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: ETYVTGGSVA HSARGLTSLF SMGAKQKLQL VNTNGSWHIN STALNCNESI NTGFIAGLFY YHKFNSTGCP QRLSSCKPII SFRQGWGPL TDANITGPSD DRPYCWHYAP RPCSVVPASS VCGPVYCFTP SPVVVGTTDI KGKPTYNWGE NETDVFLLES L RPPSGRWF ...String:
ETYVTGGSVA HSARGLTSLF SMGAKQKLQL VNTNGSWHIN STALNCNESI NTGFIAGLFY YHKFNSTGCP QRLSSCKPII SFRQGWGPL TDANITGPSD DRPYCWHYAP RPCSVVPASS VCGPVYCFTP SPVVVGTTDI KGKPTYNWGE NETDVFLLES L RPPSGRWF GCAWMNSTGF LKTCGAPPCN IYGGGGNPGN ETDLFCPTDC FRKHPEATYS RCGAGPWLTP RCMVDYPYRL WH YPCTVNF TLFKVRMFVG GFEHRFTAAC NWTRGERCNI EDRDRSEQHP LLHSTTELAI LPCSFTPMPA LSTLGIHLHQ NIV DVQYLY GVGSDMVGWA LKWEYVVLLF LLLADARVCS CLWMMLLISQ AEA

UniProtKB: Genome polyprotein

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Macromolecule #5: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 5 / Number of copies: 2 / 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

BufferpH: 7.5
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 20 sec. / Pretreatment - Atmosphere: AIR
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) / Digitization - Dimensions - Width: 4092 pixel / Digitization - Dimensions - Height: 5760 pixel / Number grids imaged: 1 / Number real images: 13555 / 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
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

Startup modelType of model: INSILICO MODEL
Final reconstructionApplied symmetry - Point group: C2 (2 fold cyclic) / Algorithm: FOURIER SPACE / Resolution.type: BY AUTHOR / Resolution: 3.55 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 105033
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. v 3.3.1)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. v 3.3.1)
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelChain - Source name: AlphaFold / Chain - Initial model type: in silico model
RefinementSpace: REAL / Protocol: FLEXIBLE FIT / Overall B value: 100
Output model

PDB-8rjj:
HCV E1/E2 homodimer complex

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