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- EMDB-37756: Cryo-EM structure of bsAb3 Fab-Gn-Gc complex -

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Basic information

Entry
Database: EMDB / ID: EMD-37756
TitleCryo-EM structure of bsAb3 Fab-Gn-Gc complex
Map data
Sample
  • Complex: the structure of bsAb3_Gn_Gc complex
    • Complex: Gn_Gc
      • Protein or peptide: Glycoprotein C
      • Protein or peptide: Glycoprotein N
    • Complex: Fab
      • Protein or peptide: bsAb3 Fab-heavy chain
      • Protein or peptide: bsAb3 Fab-light chain
KeywordsComplex / VIRAL PROTEIN / PROTEIN BINDING
Function / homology
Function and homology information


host cell Golgi membrane / entry receptor-mediated virion attachment to host cell / host cell endoplasmic reticulum membrane / symbiont entry into host cell / fusion of virus membrane with host endosome membrane / virion membrane / membrane
Similarity search - Function
Phlebovirus glycoprotein G1 / Phlebovirus glycoprotein G1 / Phlebovirus glycoprotein G2, fusion domain / Phlebovirus glycoprotein G2, C-terminal domain / Phlebovirus glycoprotein G2 fusion domain / Phlebovirus glycoprotein G2 C-terminal domain
Similarity search - Domain/homology
Envelopment polyprotein
Similarity search - Component
Biological speciesDabie bandavirus / Homo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.27 Å
AuthorsWu Y / Sun JQ
Funding support China, 2 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)32090014 China
National Natural Science Foundation of China (NSFC)82022042 China
CitationJournal: Proc Natl Acad Sci U S A / Year: 2024
Title: Bispecific antibodies targeting two glycoproteins on SFTSV exhibit synergistic neutralization and protection in a mouse model.
Authors: Zhen Chang / Dan Gao / Liying Liao / Junqing Sun / Gen Zhang / Xue Zhang / Feiran Wang / Chunrui Li / Babayemi Olawale Oladejo / Shihua Li / Yan Chai / Yongfei Hu / Xuancheng Lu / Haixia ...Authors: Zhen Chang / Dan Gao / Liying Liao / Junqing Sun / Gen Zhang / Xue Zhang / Feiran Wang / Chunrui Li / Babayemi Olawale Oladejo / Shihua Li / Yan Chai / Yongfei Hu / Xuancheng Lu / Haixia Xiao / Jianxun Qi / Zhihai Chen / Feng Gao / Yan Wu /
Abstract: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease with a high fatality rate of up to 30% caused by SFTS virus (SFTSV). However, no specific vaccine or antiviral ...Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease with a high fatality rate of up to 30% caused by SFTS virus (SFTSV). However, no specific vaccine or antiviral therapy has been approved for clinical use. To develop an effective treatment, we isolated a panel of human monoclonal antibodies (mAbs). SF5 and SF83 are two neutralizing mAbs that recognize two viral glycoproteins (Gn and Gc), respectively. We found that their epitopes are closely located, and we then engineered them as several bispecific antibodies (bsAbs). Neutralization and animal experiments indicated that bsAbs display more potent protective effects than the parental mAbs, and the cryoelectron microscopy structure of a bsAb3 Fab-Gn-Gc complex elucidated the mechanism of protection. In vivo virus passage in the presence of antibodies indicated that two bsAbs resulted in less selective pressure and could efficiently bind to all single parental mAb-escape mutants. Furthermore, epitope analysis of the protective mAbs against SFTSV and RVFV indicated that they are all located on the Gn subdomain I, where may be the hot spots in the phleboviruses. Collectively, these data provide potential therapeutic agents and molecular basis for the rational design of vaccines against SFTSV infection.
History
DepositionOct 12, 2023-
Header (metadata) releaseJun 12, 2024-
Map releaseJun 12, 2024-
UpdateJun 12, 2024-
Current statusJun 12, 2024Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_37756.png

Downloads & links

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Map

FileDownload / File: emd_37756.map.gz / Format: CCP4 / Size: 325 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.69 Å
Density
Contour LevelBy AUTHOR: 0.023
Minimum - Maximum-0.0018139291 - 2.1652436
Average (Standard dev.)0.0007554047 (±0.018431028)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions440440440
Spacing440440440
CellA=B=C: 303.6 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_37756_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_37756_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 : the structure of bsAb3_Gn_Gc complex

EntireName: the structure of bsAb3_Gn_Gc complex
Components
  • Complex: the structure of bsAb3_Gn_Gc complex
    • Complex: Gn_Gc
      • Protein or peptide: Glycoprotein C
      • Protein or peptide: Glycoprotein N
    • Complex: Fab
      • Protein or peptide: bsAb3 Fab-heavy chain
      • Protein or peptide: bsAb3 Fab-light chain

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Supramolecule #1: the structure of bsAb3_Gn_Gc complex

SupramoleculeName: the structure of bsAb3_Gn_Gc complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all

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Supramolecule #2: Gn_Gc

SupramoleculeName: Gn_Gc / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1, #4
Source (natural)Organism: Dabie bandavirus

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Supramolecule #3: Fab

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

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Macromolecule #1: Glycoprotein C

MacromoleculeName: Glycoprotein C / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Dabie bandavirus
Molecular weightTheoretical: 47.204645 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: CDEMVHADSK LVSCRQGSGN MKECVTTGRA LLPAVNPGQE ACLHFTAPGS PDSKCLKIKV KRINLKCKKS SSYFVPDARS RCTSVRRCR WAGDCQSGCP PHFTSNSFSD DWAGKMDRAG LGFSGCSDGC GGAACGCFNA APSCIFWRKW VENPHGIIWK V SPCVAWVP ...String:
CDEMVHADSK LVSCRQGSGN MKECVTTGRA LLPAVNPGQE ACLHFTAPGS PDSKCLKIKV KRINLKCKKS SSYFVPDARS RCTSVRRCR WAGDCQSGCP PHFTSNSFSD DWAGKMDRAG LGFSGCSDGC GGAACGCFNA APSCIFWRKW VENPHGIIWK V SPCVAWVP SAVIELTMPS GEVRTFHPMS GIPTQVFKGV SVTYLGSDME VSGLTDLCEI EELKSKKLAL APCNQAGMGV VG KVGEIQC SSEESARTIK KDGCIWNADL VGIELRVDDA VCYSKITSVE AVANYSAIPT TIGGLRFERS HDSQGKISGS PLD ITAIRG SFSVNYRGLR LSLSEITATC TGEVTNVSGC YSCMTGAKVS IKLHSSKNST AHVRCKGDET AFSVLEGVHS YTVS LSFDH AVVDEQCQLN CGGHESQVTL KGNLIFLDHH HHHH

UniProtKB: Envelopment polyprotein

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Macromolecule #2: bsAb3 Fab-heavy chain

MacromoleculeName: bsAb3 Fab-heavy chain / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 37.968289 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: EVQLVESGGG LVKPGGSLRL SCAASGFTFS NAWMSWVRQA PGKGLEWVGR IKSKTDGGTT DYAAPVKGRF TISRDDSKNT LYLQMNSLK TEDTAVYYCT TDFISAGPWY FDLWGRGTLV TVSSGGGGSG GGGSQVQLVQ SGGGVVKTGR SQRVSCATSG F TFSSYAIH ...String:
EVQLVESGGG LVKPGGSLRL SCAASGFTFS NAWMSWVRQA PGKGLEWVGR IKSKTDGGTT DYAAPVKGRF TISRDDSKNT LYLQMNSLK TEDTAVYYCT TDFISAGPWY FDLWGRGTLV TVSSGGGGSG GGGSQVQLVQ SGGGVVKTGR SQRVSCATSG F TFSSYAIH WVRQAPGKGL EWVAVISYDG SNKYYADSVK GRFTISRDSS KNTVYLQMNS LRTEDTAVYY CARSQASWQA FD YWGQGTL VTVSSASTKG PSVFPLAPSS KSTSGGTAAL GCLVKDYFPE PVTVSWNSGA LTSGVHTFPA VLQSSGLYSL SSV VTVPSS SLGTQTYICN VNHKPSNTKV DKKVEPKSCD K

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Macromolecule #3: bsAb3 Fab-light chain

MacromoleculeName: bsAb3 Fab-light chain / type: protein_or_peptide / ID: 3 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 35.276727 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: SSELTQDPAV SVALGQTVRI TCQGDSLRSY YASWYQQKPG QAPVLVIYGK NNRPSGIPDR FSGSSSGNTA SLTITGAQAE DEADYYCNS RDSSGNHVVF GGGTKLTVLG GGGSGGGGSD IQMTQSPSSL SASVGDRVTI TCRASQGVGT DLAWYQQKPG K APNRLIFA ...String:
SSELTQDPAV SVALGQTVRI TCQGDSLRSY YASWYQQKPG QAPVLVIYGK NNRPSGIPDR FSGSSSGNTA SLTITGAQAE DEADYYCNS RDSSGNHVVF GGGTKLTVLG GGGSGGGGSD IQMTQSPSSL SASVGDRVTI TCRASQGVGT DLAWYQQKPG K APNRLIFA ASNLQSGVPS RFSGSGSGTE FTLTISSLQP EDFATYYCLH HNSFPLAFGG GTKVEIKRTV AAPSVFIFPP SD EQLKSGT ASVVCLLNNF YPREAKVQWK VDNALQSGNS QESVTEQDSK DSTYSLSSTL TLSKADYEKH KVYACEVTHQ GLS SPVTKS FNRGECS

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Macromolecule #4: Glycoprotein N

MacromoleculeName: Glycoprotein N / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Dabie bandavirus
Molecular weightTheoretical: 35.780461 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: DGIQDSGPII CAGPIHSNKS ADIPHLLGYS EKICQIDRLI HVSSWLRNHS QFQGYVGQRG GRSQVSYYPA ENSYSRWSGL LSPCDADWL GMLVVKKAKG SDMIVPGPSY KGKVFFERPT FDGYVGWGCG SGKSRTESGE LCSSDSGTSS GLLPSDRVLW I GDVACQPM ...String:
DGIQDSGPII CAGPIHSNKS ADIPHLLGYS EKICQIDRLI HVSSWLRNHS QFQGYVGQRG GRSQVSYYPA ENSYSRWSGL LSPCDADWL GMLVVKKAKG SDMIVPGPSY KGKVFFERPT FDGYVGWGCG SGKSRTESGE LCSSDSGTSS GLLPSDRVLW I GDVACQPM TPIPEETFLE LKSFSQSEFP DICKIDGIVF NQCEGESLPQ PFDVAWMDVG HSHKIIMREH KTKWVQESSS KD FVCYKEG TGPCSESEEK TCKTSGSCRG DMQFCKVAGC EHGEEASEAK CRCSLVHKPG EVVVSYGGMR VRPKCYGFSR MMA TLEVN

UniProtKB: Envelopment polyprotein

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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: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.27 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 158475
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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