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- EMDB-43604: CCHFV GP38 bound to ADI-46152 and ADI-58048 Fabs -

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Basic information

Entry
Database: EMDB / ID: EMD-43604
TitleCCHFV GP38 bound to ADI-46152 and ADI-58048 Fabs
Map dataSharpened map
Sample
  • Complex: CCHFV GP38 bound with ADI-46152 and ADI-58048 Fabs
    • Complex: ADI-46152 Fab
      • Protein or peptide: ADI-46152 Fab Heavy Chain
      • Protein or peptide: ADI-46152 Fab Light Chain
    • Complex: CCHFV GP38
      • Protein or peptide: GP38
    • Complex: ADI-58048 Fab
      • Protein or peptide: ADI-58048 Fab Heavy Chain
      • Protein or peptide: ADI-58048 Fab Light Chain
KeywordsCCHFV / GP38 / Antibody / Immunology / VIRAL PROTEIN / VIRAL PROTEIN-IMMUNE SYSTEM complex
Function / homology
Function and homology information


host cell Golgi membrane / clathrin-dependent endocytosis of virus by host cell / host cell endoplasmic reticulum membrane / virus-mediated perturbation of host defense response / fusion of virus membrane with host endosome membrane / viral envelope / virion attachment to host cell / virion membrane / membrane
Similarity search - Function
: / : / : / : / Nairovirus, structural glycoprotein Gn / Nairovirus, mucin-like domain / Nairovirus NSm / Nairovirus M polyprotein-like / Nairovirus GP38 / : ...: / : / : / : / Nairovirus, structural glycoprotein Gn / Nairovirus, mucin-like domain / Nairovirus NSm / Nairovirus M polyprotein-like / Nairovirus GP38 / : / Hantavirus glycoprotein Gc, C-terminal / Hantavirus glycoprotein Gc / Hantavirus glycoprotein Gc, N-terminal
Similarity search - Domain/homology
Envelopment polyprotein
Similarity search - Component
Biological speciesHomo sapiens (human) / Crimean-Congo hemorrhagic fever virus / Crimean-Congo hemorrhagic fever virus strain IbAr10200
Methodsingle particle reconstruction / cryo EM / Resolution: 3.9 Å
AuthorsHjorth CK / McLellan JS
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R01AI152246 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)U19AI142777 United States
CitationJournal: Cell Rep / Year: 2024
Title: Crimean-Congo hemorrhagic fever survivors elicit protective non-neutralizing antibodies that target 11 overlapping regions on glycoprotein GP38.
Authors: Olivia S Shin / Stephanie R Monticelli / Christy K Hjorth / Vladlena Hornet / Michael Doyle / Dafna Abelson / Ana I Kuehne / Albert Wang / Russell R Bakken / Akaash K Mishra / Marissa ...Authors: Olivia S Shin / Stephanie R Monticelli / Christy K Hjorth / Vladlena Hornet / Michael Doyle / Dafna Abelson / Ana I Kuehne / Albert Wang / Russell R Bakken / Akaash K Mishra / Marissa Middlecamp / Elizabeth Champney / Lauran Stuart / Daniel P Maurer / Jiannan Li / Jacob Berrigan / Jennifer Barajas / Stephen Balinandi / Julius J Lutwama / Leslie Lobel / Larry Zeitlin / Laura M Walker / John M Dye / Kartik Chandran / Andrew S Herbert / Noel T Pauli / Jason S McLellan /
Abstract: Crimean-Congo hemorrhagic fever virus can cause lethal disease in humans yet there are no approved medical countermeasures. Viral glycoprotein GP38, exclusive to Nairoviridae, is a target of ...Crimean-Congo hemorrhagic fever virus can cause lethal disease in humans yet there are no approved medical countermeasures. Viral glycoprotein GP38, exclusive to Nairoviridae, is a target of protective antibodies and is a key antigen in preclinical vaccine candidates. Here, we isolate 188 GP38-specific antibodies from human survivors of infection. Competition experiments show that these antibodies bind across 5 distinct antigenic sites, encompassing 11 overlapping regions. Additionally, we show structures of GP38 bound with 9 of these antibodies targeting different antigenic sites. Although these GP38-specific antibodies are non-neutralizing, several display protective efficacy equal to or better than murine antibody 13G8 in two highly stringent rodent models of infection. Together, these data expand our understanding regarding this important viral protein and may inform the development of broadly effective CCHFV antibody therapeutics.
History
DepositionFeb 2, 2024-
Header (metadata) releaseJul 24, 2024-
Map releaseJul 24, 2024-
UpdateJul 24, 2024-
Current statusJul 24, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_43604.png

Downloads & links

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Map

FileDownload / File: emd_43604.map.gz / Format: CCP4 / Size: 274.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationSharpened map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 416 pix.
= 346.611 Å		0.83 Å/pix.
x 416 pix.
= 346.611 Å		0.83 Å/pix.
x 416 pix.
= 346.611 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.8332 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.18
Minimum - Maximum-0.7909513 - 0.9755338
Average (Standard dev.)0.00000530654 (±0.012707646)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions416416416
Spacing416416416
CellA=B=C: 346.6112 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Half map A

Fileemd_43604_half_map_1.map
AnnotationHalf map A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map B

Fileemd_43604_half_map_2.map
AnnotationHalf map B
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : CCHFV GP38 bound with ADI-46152 and ADI-58048 Fabs

EntireName: CCHFV GP38 bound with ADI-46152 and ADI-58048 Fabs
Components
  • Complex: CCHFV GP38 bound with ADI-46152 and ADI-58048 Fabs
    • Complex: ADI-46152 Fab
      • Protein or peptide: ADI-46152 Fab Heavy Chain
      • Protein or peptide: ADI-46152 Fab Light Chain
    • Complex: CCHFV GP38
      • Protein or peptide: GP38
    • Complex: ADI-58048 Fab
      • Protein or peptide: ADI-58048 Fab Heavy Chain
      • Protein or peptide: ADI-58048 Fab Light Chain

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Supramolecule #1: CCHFV GP38 bound with ADI-46152 and ADI-58048 Fabs

SupramoleculeName: CCHFV GP38 bound with ADI-46152 and ADI-58048 Fabs / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all

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Supramolecule #2: ADI-46152 Fab

SupramoleculeName: ADI-46152 Fab / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #2-#3
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #3: CCHFV GP38

SupramoleculeName: CCHFV GP38 / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #1
Source (natural)Organism: Crimean-Congo hemorrhagic fever virus / Strain: IbAr10200

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Supramolecule #4: ADI-58048 Fab

SupramoleculeName: ADI-58048 Fab / type: complex / ID: 4 / Parent: 1 / Macromolecule list: #4-#5
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: GP38

MacromoleculeName: GP38 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Crimean-Congo hemorrhagic fever virus strain IbAr10200
Strain: IbAr10200
Molecular weightTheoretical: 30.241828 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: NLKMEIILTL SQGLKKYYGK ILRLLQLTLE EDTEGLLEWC KRNLGLDCDD TFFQKRIEEF FITGEGHFNE VLQFRTPGTL STTESTPAG LPTAEPFKSY FAKGFLSIDS GYYSAKCYSG TSNSGLQLIN ITRHSTRIVD TPGPKITNLK TINCINLKAS I FKEHREVE ...String:
NLKMEIILTL SQGLKKYYGK ILRLLQLTLE EDTEGLLEWC KRNLGLDCDD TFFQKRIEEF FITGEGHFNE VLQFRTPGTL STTESTPAG LPTAEPFKSY FAKGFLSIDS GYYSAKCYSG TSNSGLQLIN ITRHSTRIVD TPGPKITNLK TINCINLKAS I FKEHREVE INVLLPQVAV NLSNCHVVIK SHVCDYSLDI DGAVRLPHIY HEGVFIPGTY KIVIDKKNKL NDRCTLFTDC VI KGREVRK GQSVLRQYKT EIRIGKASTG S

UniProtKB: Envelopment polyprotein

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Macromolecule #2: ADI-46152 Fab Heavy Chain

MacromoleculeName: ADI-46152 Fab Heavy Chain / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 24.370311 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: EVQLVESGGV LVQPGGSLRL SCAASGFTVN SNYMTWVRQA PGKGLEWVSV IYSGGYTYYA DSVKGRFAIS RDNSKNTVYL QMNSLRVED TAVYYCARLR LSSSWYPEAF DYWGQGTLVT VSSASTKGPS VFPLAPSSKS TSGGTAALGC LVKDYFPEPV T VSWNSGAL ...String:
EVQLVESGGV LVQPGGSLRL SCAASGFTVN SNYMTWVRQA PGKGLEWVSV IYSGGYTYYA DSVKGRFAIS RDNSKNTVYL QMNSLRVED TAVYYCARLR LSSSWYPEAF DYWGQGTLVT VSSASTKGPS VFPLAPSSKS TSGGTAALGC LVKDYFPEPV T VSWNSGAL TSGVHTFPAV LQSSGLYSLS SVVTVPSSSL GTQTYICNVN HKPSNTKVDK KVEPKSCDKG

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Macromolecule #3: ADI-46152 Fab Light Chain

MacromoleculeName: ADI-46152 Fab Light Chain / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 22.957463 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: AILLTQSPSS LSASVGDRVT ITCRASQGIS SALAWYQQKP GRAPKVLIYD ASSLANGVPS RFSGSGSGTD FTLTINSLQP EDFATYYCQ QFNYYPLTFG GGTKVEIKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF YPREAKVQWK VDNALQSGNS Q ESVTEQDS ...String:
AILLTQSPSS LSASVGDRVT ITCRASQGIS SALAWYQQKP GRAPKVLIYD ASSLANGVPS RFSGSGSGTD FTLTINSLQP EDFATYYCQ QFNYYPLTFG GGTKVEIKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF YPREAKVQWK VDNALQSGNS Q ESVTEQDS KDSTYSLSST LTLSKADYEK HKVYACEVTQ GTTSVTKSFN RGEC

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Macromolecule #4: ADI-58048 Fab Heavy Chain

MacromoleculeName: ADI-58048 Fab Heavy Chain / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.790645 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: QLQLQESGPG LVKPSETLSL TCTVSGGSIT TSHYYWGWIR QPPGKGLEWV GSMYYSGGIY YNPSLKGRVT ISVDTSKNQF SLKLSSVTA ADTAVYYCAL ADAPDDAFDI WGQGTMVTVS SASTKGPSVF PLAPSSKSTS GGTAALGCLV KDYFPEPVTV S WNSGALTS ...String:
QLQLQESGPG LVKPSETLSL TCTVSGGSIT TSHYYWGWIR QPPGKGLEWV GSMYYSGGIY YNPSLKGRVT ISVDTSKNQF SLKLSSVTA ADTAVYYCAL ADAPDDAFDI WGQGTMVTVS SASTKGPSVF PLAPSSKSTS GGTAALGCLV KDYFPEPVTV S WNSGALTS GVHTFPAVLQ SSGLYSLSSV VTVPSSSLGT QTYICNVNHK PSNTKVDKKV EPKSCDKG

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Macromolecule #5: ADI-58048 Fab Light Chain

MacromoleculeName: ADI-58048 Fab Light Chain / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.36591 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: DIQMTQSPSS LSAFVGDRVT ITCRASQSIS SYLNWYQQKP GKAPKLLIYA ASTLQSGVPS RFSGSGSGTD FTLTISSLQS EDFATYYCQ ESYSIPFTFG PGTKVDIKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF YPREAKVQWK VDNALQSGNS Q ESVTEQDS ...String:
DIQMTQSPSS LSAFVGDRVT ITCRASQSIS SYLNWYQQKP GKAPKLLIYA ASTLQSGVPS RFSGSGSGTD FTLTISSLQS EDFATYYCQ ESYSIPFTFG PGTKVDIKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF YPREAKVQWK VDNALQSGNS Q ESVTEQDS KDSTYSLSST LTLSKADYEK HKVYACEVTH QGLSSPVTKS FNRGEC

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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
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 283 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 real images: 3647 / Average electron dose: 80.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.5 µm / Nominal magnification: 105000
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.9 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 492968
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial model
PDB IDChain

6vkf

chain_id: A, source_name: PDB, initial_model_type: experimental model
chain_id: B, source_name: AlphaFold, initial_model_type: in silico model
chain_id: C, source_name: AlphaFold, initial_model_type: in silico model
chain_id: H, source_name: AlphaFold, initial_model_type: in silico model
chain_id: L, source_name: AlphaFold, initial_model_type: in silico model
RefinementSpace: REAL / Protocol: RIGID BODY FIT
Output model

PDB-8vww:
CCHFV GP38 bound to ADI-46152 and ADI-58048 Fabs

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