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- EMDB-43551: CCHFV GP38 bound with ADI-46143 and ADI-46158 Fabs -

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Basic information

Entry
Database: EMDB / ID: EMD-43551
TitleCCHFV GP38 bound with ADI-46143 and ADI-46158 Fabs
Map data
Sample
  • Complex: CCHFV GP38 bound with ADI-46143 Fab and ADI-46158 Fab
    • Complex: ADI-46143 Fab
      • Protein or peptide: ADI-46143 Fab Heavy Chain
      • Protein or peptide: ADI-46143 Fab Light Chain
    • Complex: ADI-46158 Fab
      • Protein or peptide: ADI-46158 Fab Heavy Chain
      • Protein or peptide: ADI-46158 Fab Light Chain
    • Complex: CCHFV GP38
      • Protein or peptide: CCHFV GP38
KeywordsCCHFV / GP38 / Antibody / Immunology / VIRAL PROTEIN
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 M polyprotein-like / : / : / : / : / Nairovirus GP38 / Nairovirus, structural glycoprotein Gn / Nairovirus, mucin-like domain / Nairovirus NSm / Hantavirus glycoprotein Gc ...Nairovirus M polyprotein-like / : / : / : / : / Nairovirus GP38 / Nairovirus, structural glycoprotein Gn / Nairovirus, mucin-like domain / Nairovirus NSm / Hantavirus glycoprotein Gc / : / Hantavirus glycoprotein Gc, N-terminal / Hantavirus glycoprotein Gc, C-terminal
Similarity search - Domain/homology
Envelopment polyprotein
Similarity search - Component
Biological speciesHomo sapiens (human) / Crimean-Congo hemorrhagic fever virus
Methodsingle particle reconstruction / cryo EM / Resolution: 5.6 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
DepositionJan 30, 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_43551.png

Downloads & links

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Map

FileDownload / File: emd_43551.map.gz / Format: CCP4 / Size: 274.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 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: 0.12
Minimum - Maximum-0.2690141 - 0.5281387
Average (Standard dev.)0.0001294525 (±0.0109507395)
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: #1

Fileemd_43551_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_43551_half_map_2.map
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-46143 Fab and ADI-46158 Fab

EntireName: CCHFV GP38 bound with ADI-46143 Fab and ADI-46158 Fab
Components
  • Complex: CCHFV GP38 bound with ADI-46143 Fab and ADI-46158 Fab
    • Complex: ADI-46143 Fab
      • Protein or peptide: ADI-46143 Fab Heavy Chain
      • Protein or peptide: ADI-46143 Fab Light Chain
    • Complex: ADI-46158 Fab
      • Protein or peptide: ADI-46158 Fab Heavy Chain
      • Protein or peptide: ADI-46158 Fab Light Chain
    • Complex: CCHFV GP38
      • Protein or peptide: CCHFV GP38

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Supramolecule #1: CCHFV GP38 bound with ADI-46143 Fab and ADI-46158 Fab

SupramoleculeName: CCHFV GP38 bound with ADI-46143 Fab and ADI-46158 Fab / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all

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Supramolecule #2: ADI-46143 Fab

SupramoleculeName: ADI-46143 Fab / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #2-#3
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #3: ADI-46158 Fab

SupramoleculeName: ADI-46158 Fab / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #4-#5
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #4: CCHFV GP38

SupramoleculeName: CCHFV GP38 / type: complex / ID: 4 / Parent: 1 / Macromolecule list: #1
Source (natural)Organism: Crimean-Congo hemorrhagic fever virus / Strain: IbAr10200

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Macromolecule #1: CCHFV GP38

MacromoleculeName: CCHFV GP38 / type: protein_or_peptide / ID: 1 / Enantiomer: LEVO
Source (natural)Organism: Crimean-Congo hemorrhagic fever virus / Strain: IbAr10200
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: NLKMEIILTL SQGLKKYYGK ILRLLQLTLE EDTEGLLEWC KRNLGLDCDD TFFQKRIEEF FITGEGHFNE VLQFRTPGTL STTESTPAGL PTAEPFKSYF AKGFLSIDSG YYSAKCYSGT SNSGLQLINI TRHSTRIVDT PGPKITNLKT INCINLKASI FKEHREVEIN ...String:
NLKMEIILTL SQGLKKYYGK ILRLLQLTLE EDTEGLLEWC KRNLGLDCDD TFFQKRIEEF FITGEGHFNE VLQFRTPGTL STTESTPAGL PTAEPFKSYF AKGFLSIDSG YYSAKCYSGT SNSGLQLINI TRHSTRIVDT PGPKITNLKT INCINLKASI FKEHREVEIN VLLPQVAVNL SNCHVVIKSH VCDYSLDIDG AVRLPHIYHE GVFIPGTYKI VIDKKNKLND RCTLFTDCVI KGREVRKGQS VLRQYKTEIR IGKASTGS

UniProtKB: Envelopment polyprotein

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Macromolecule #2: ADI-46143 Fab Heavy Chain

MacromoleculeName: ADI-46143 Fab Heavy Chain / type: protein_or_peptide / ID: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: QLQLQESGPG LEKPSETLSL TCIVSGGSIS SSDYFWGWIR QPPGKGLEWI GSIYYSGSTY YNPSLKSRVT TSVDTSKNQF SLKVMSVTAA DTAMYYCARG GYGGYESDAY DIWGQGTMVT VSSASTKGPS VFPLAPSSKS TSGGTAALGC LVKDYFPEPV TVSWNSGALT ...String:
QLQLQESGPG LEKPSETLSL TCIVSGGSIS SSDYFWGWIR QPPGKGLEWI GSIYYSGSTY YNPSLKSRVT TSVDTSKNQF SLKVMSVTAA DTAMYYCARG GYGGYESDAY DIWGQGTMVT VSSASTKGPS VFPLAPSSKS TSGGTAALGC LVKDYFPEPV TVSWNSGALT SGVHTFPAVL QSSGLYSLSS VVTVPSSSLG TQTYICNVNH KPSNTKVDKK VEPK

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Macromolecule #3: ADI-46143 Fab Light Chain

MacromoleculeName: ADI-46143 Fab Light Chain / type: protein_or_peptide / ID: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: SYVLTQPPSV SVAPGQTAKI TCGGNNIGGK SVHWYQQKPG QAPVLVVYDD SDRPSGIPER FSGSNSGNTA TLTISRVEAG DEAGYFCQVW DGSGDQVVFG GGTKLTVLQP KAAPSVTLFP PSSEELQANK ATLVCLISDF YPGAVTVAWK ADSSPVKAGV ETTTPSKQSN ...String:
SYVLTQPPSV SVAPGQTAKI TCGGNNIGGK SVHWYQQKPG QAPVLVVYDD SDRPSGIPER FSGSNSGNTA TLTISRVEAG DEAGYFCQVW DGSGDQVVFG GGTKLTVLQP KAAPSVTLFP PSSEELQANK ATLVCLISDF YPGAVTVAWK ADSSPVKAGV ETTTPSKQSN NKYAASSYLS LTPEQWKSHR SYSCQVTHEG STVEKTVAPT ECS

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Macromolecule #4: ADI-46158 Fab Heavy Chain

MacromoleculeName: ADI-46158 Fab Heavy Chain / type: protein_or_peptide / ID: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: EVQLVESGGG VVQPGRSLRL SCAASGFTFS SYGMHWVRQA PGKGPEWVAV ILYDGSYKYY KDSVKGRFTI SRDNSNNTLY LQMNSLRPED TAVYYCARVH KPLYGDYYFD YWGQGTLVTV SSASTKGPSV FPLAPSSKST SGGTAALGCL VKDYFPEPVT VSWNSGALTS ...String:
EVQLVESGGG VVQPGRSLRL SCAASGFTFS SYGMHWVRQA PGKGPEWVAV ILYDGSYKYY KDSVKGRFTI SRDNSNNTLY LQMNSLRPED TAVYYCARVH KPLYGDYYFD YWGQGTLVTV SSASTKGPSV FPLAPSSKST SGGTAALGCL VKDYFPEPVT VSWNSGALTS GVHTFPAVLQ SSGLYSLSSV VTVPSSSLGT QTYICNVNHK PSNTKVDKKV EPKSCDKG

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Macromolecule #5: ADI-46158 Fab Light Chain

MacromoleculeName: ADI-46158 Fab Light Chain / type: protein_or_peptide / ID: 5 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: ETTLTQSPSS LSASIGDRVT ITCRASQDIR SALAWYQQKP GKAPKLLIYD ASTLQSGVPS RFTGGGSGTD FTLTISSLQP EDFATYYCQQ VYSYPVTFGQ GTRLEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ ESVTEQDSKD ...String:
ETTLTQSPSS LSASIGDRVT ITCRASQDIR SALAWYQQKP GKAPKLLIYD ASTLQSGVPS RFTGGGSGTD FTLTISSLQP EDFATYYCQQ VYSYPVTFGQ GTRLEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC

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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

Concentration0.4 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: 1485 / 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: 5.6 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 68137
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelChain - Chain ID: F / Chain - Source name: AlphaFold / Chain - Initial model type: in silico model

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