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- EMDB-40272: BtCoV-422 in complex with neutralizing antibody JC57-11 -

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Basic information

Entry
Database: EMDB / ID: EMD-40272
TitleBtCoV-422 in complex with neutralizing antibody JC57-11
Map data
Sample
  • Complex: btCoV-422 in complex with JC57-11 Fab
    • Complex: btCoV-422 spike
      • Protein or peptide: Spike glycoproteinSpike protein
    • Complex: JC57-11 Fab
      • Protein or peptide: JC57-11 Fab heavy chain
      • Protein or peptide: JC57-11 Fab light chain
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
Keywordscoronavirus / MERS / neutralizing / antibody / MERS-like / merbecovirus / bat / virus / CDRH3 / RBD / VIRAL PROTEIN / VIRAL PROTEIN-IMMUNE SYSTEM complex
Function / homology
Function and homology information


endocytosis involved in viral entry into host cell / host cell endoplasmic reticulum-Golgi intermediate compartment membrane / receptor-mediated virion attachment to host cell / fusion of virus membrane with host plasma membrane / fusion of virus membrane with host endosome membrane / viral envelope / host cell plasma membrane / virion membrane / membrane
Similarity search - Function
Spike (S) protein S1 subunit, receptor-binding domain, HKU4-like / Spike (S) protein S1 subunit, N-terminal domain, MERS-CoV-like / Spike glycoprotein S2, coronavirus, C-terminal / Coronavirus spike glycoprotein S2, intravirion / Betacoronavirus spike (S) glycoprotein S1 subunit N-terminal (NTD) domain profile. / Spike glycoprotein, N-terminal domain superfamily / Betacoronavirus spike (S) glycoprotein S1 subunit C-terminal (CTD) domain profile. / Spike glycoprotein, betacoronavirus / Spike (S) protein S1 subunit, receptor-binding domain, betacoronavirus / Spike S1 subunit, receptor binding domain superfamily, betacoronavirus ...Spike (S) protein S1 subunit, receptor-binding domain, HKU4-like / Spike (S) protein S1 subunit, N-terminal domain, MERS-CoV-like / Spike glycoprotein S2, coronavirus, C-terminal / Coronavirus spike glycoprotein S2, intravirion / Betacoronavirus spike (S) glycoprotein S1 subunit N-terminal (NTD) domain profile. / Spike glycoprotein, N-terminal domain superfamily / Betacoronavirus spike (S) glycoprotein S1 subunit C-terminal (CTD) domain profile. / Spike glycoprotein, betacoronavirus / Spike (S) protein S1 subunit, receptor-binding domain, betacoronavirus / Spike S1 subunit, receptor binding domain superfamily, betacoronavirus / Betacoronavirus spike glycoprotein S1, receptor binding / Spike glycoprotein S1, N-terminal domain, betacoronavirus-like / Betacoronavirus-like spike glycoprotein S1, N-terminal / Spike glycoprotein S2, coronavirus, heptad repeat 1 / Spike glycoprotein S2, coronavirus, heptad repeat 2 / Coronavirus spike (S) glycoprotein S2 subunit heptad repeat 2 (HR2) region profile. / Coronavirus spike (S) glycoprotein S2 subunit heptad repeat 1 (HR1) region profile. / Spike glycoprotein S2 superfamily, coronavirus / Spike glycoprotein S2, coronavirus / Coronavirus spike glycoprotein S2 / Coronavirus spike glycoprotein S1, C-terminal / Coronavirus spike glycoprotein S1, C-terminal
Similarity search - Domain/homology
Biological speciesMiddle East respiratory syndrome-related coronavirus / Macaca (macaques)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.0 Å
AuthorsMcFadden E / McLellan JS
Funding support United States, 1 items
OrganizationGrant numberCountry
Bill & Melinda Gates Foundation26-7535-3450 United States
CitationJournal: Sci Transl Med / Year: 2023
Title: A MERS-CoV antibody neutralizes a pre-emerging group 2c bat coronavirus.
Authors: Longping V Tse / Yixuan J Hou / Elizabeth McFadden / Rhianna E Lee / Trevor D Scobey / Sarah R Leist / David R Martinez / Rita M Meganck / Alexandra Schäfer / Boyd L Yount / Teresa Mascenik ...Authors: Longping V Tse / Yixuan J Hou / Elizabeth McFadden / Rhianna E Lee / Trevor D Scobey / Sarah R Leist / David R Martinez / Rita M Meganck / Alexandra Schäfer / Boyd L Yount / Teresa Mascenik / John M Powers / Scott H Randell / Yi Zhang / Lingshu Wang / John Mascola / Jason S McLellan / Ralph S Baric /
Abstract: The repeated emergence of zoonotic human betacoronaviruses (β-CoVs) dictates the need for broad therapeutics and conserved epitope targets for countermeasure design. Middle East respiratory syndrome ...The repeated emergence of zoonotic human betacoronaviruses (β-CoVs) dictates the need for broad therapeutics and conserved epitope targets for countermeasure design. Middle East respiratory syndrome (MERS)-related coronaviruses (CoVs) remain a pressing concern for global health preparedness. Using metagenomic sequence data and CoV reverse genetics, we recovered a full-length wild-type MERS-like BtCoV//GD/2014-422 (BtCoV-422) recombinant virus, as well as two reporter viruses, and evaluated their human emergence potential and susceptibility to currently available countermeasures. Similar to MERS-CoV, BtCoV-422 efficiently used human and other mammalian dipeptidyl peptidase protein 4 (DPP4) proteins as entry receptors and an alternative DPP4-independent infection route in the presence of exogenous proteases. BtCoV-422 also replicated efficiently in primary human airway, lung endothelial, and fibroblast cells, although less efficiently than MERS-CoV. However, BtCoV-422 shows minor signs of infection in 288/330 human DPP4 transgenic mice. Several broad CoV antivirals, including nucleoside analogs and 3C-like/M protease inhibitors, demonstrated potent inhibition against BtCoV-422 in vitro. Serum from mice that received a MERS-CoV mRNA vaccine showed reduced neutralizing activity against BtCoV-422. Although most MERS-CoV-neutralizing monoclonal antibodies (mAbs) had limited activity, one anti-MERS receptor binding domain mAb, JC57-11, neutralized BtCoV-422 potently. A cryo-electron microscopy structure of JC57-11 in complex with BtCoV-422 spike protein revealed the mechanism of cross-neutralization involving occlusion of the DPP4 binding site, highlighting its potential as a broadly neutralizing mAb for group 2c CoVs that use DPP4 as a receptor. These studies provide critical insights into MERS-like CoVs and provide candidates for countermeasure development.
History
DepositionApr 1, 2023-
Header (metadata) releaseOct 4, 2023-
Map releaseOct 4, 2023-
UpdateOct 4, 2023-
Current statusOct 4, 2023Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_40272.png

Downloads & links

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Map

FileDownload / File: emd_40272.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.8332 Å
Density
Contour LevelBy EMDB: 1.0
Minimum - Maximum-7.3040853 - 158.846830000000011
Average (Standard dev.)0.009841617 (±1.1899344)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions400400400
Spacing400400400
CellA=B=C: 333.28 Å
α=β=γ: 90.0 °

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Supplemental data

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Sample components

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Entire : btCoV-422 in complex with JC57-11 Fab

EntireName: btCoV-422 in complex with JC57-11 Fab
Components
  • Complex: btCoV-422 in complex with JC57-11 Fab
    • Complex: btCoV-422 spike
      • Protein or peptide: Spike glycoproteinSpike protein
    • Complex: JC57-11 Fab
      • Protein or peptide: JC57-11 Fab heavy chain
      • Protein or peptide: JC57-11 Fab light chain
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: btCoV-422 in complex with JC57-11 Fab

SupramoleculeName: btCoV-422 in complex with JC57-11 Fab / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Molecular weightTheoretical: 650 KDa

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Supramolecule #2: btCoV-422 spike

SupramoleculeName: btCoV-422 spike / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1
Source (natural)Organism: Middle East respiratory syndrome-related coronavirus
Molecular weightTheoretical: 600 KDa

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Supramolecule #3: JC57-11 Fab

SupramoleculeName: JC57-11 Fab / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #2-#3
Source (natural)Organism: Macaca (macaques)
Molecular weightTheoretical: 50 KDa

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Macromolecule #1: Spike glycoprotein

MacromoleculeName: Spike glycoprotein / type: protein_or_peptide / ID: 1 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Middle East respiratory syndrome-related coronavirus
Molecular weightTheoretical: 142.101109 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MRLSVCLLMF LLTPIKGDVD SGPPSSATSC KEADMRNSSS EFFNKQWPMP INASKADGII YPTGKSYSNI SLTLQGLFPK HGDLGEQYI YSVGHSDSNY DYLGKLFVSD YATKVVPFNN GFVVRIGAAA NATGSVIIST VQKTIKKIYP AFMLGSSVGN F SNGVSGRY ...String:
MRLSVCLLMF LLTPIKGDVD SGPPSSATSC KEADMRNSSS EFFNKQWPMP INASKADGII YPTGKSYSNI SLTLQGLFPK HGDLGEQYI YSVGHSDSNY DYLGKLFVSD YATKVVPFNN GFVVRIGAAA NATGSVIIST VQKTIKKIYP AFMLGSSVGN F SNGVSGRY FNHTLLLLPD GCGTRLWALY CVIEPRNGSY CPGNSNYNTF AVFDTPHTDC TSAGYNTNAT LNSFKEYFDL QN CSFIYSF NITEDENAEW FGITQNTQGV HLYSSRKGDL YGSNMFLFAT LPVYDGIKYY TVIPRSIRSK YSERQAWAAF YIY SLHKLT YLLDFSVDGY IRRAVDCGHD DLSQLYCSYE SFDVGSGVYS VSSFEVHSRG QFIEQPNSVE CDFTKLLSGT PPQV YNFNR LVFTNCNYNL TKLLSLFMVN EFSCDGISPD AIARGCYSSL TVDYFAYPLS MKSYMQPGSA GVISQYNYKQ SFANP TCRI FATAPANLTI TKPSSYSFIS KCSRLTGDNS HIETPIVINP GEYSICKNFA PNGFSQDGDY FTRQLSQLEG GGILVG VGS VTPMTDTLQM GFIISVQYGT DTNSVCPMMD LGNSTTITDK LGVCVEYNLY GVSGRGVFIN CTAVGVKQQR FVYDGFD NL IGYYSDDGNY YCVRPCVSVP LSVVYDKTTN SHATIFGSVA CEHITTMLHQ FSRTTQASLR MRDVSNSGPL QTAVGCVI G LVNSSMVVDN CQLPLGQSLC AVPSTTRSSS QLQLATINYT QPQLLSPLNS SGFVVQVPTN FSFGITQEYI QTTIQKVTV DCKQYVCNGF QKCEQLLREY GQFCAKINQA LHGANLMQDE SVANLFSDIK THKSQPLNAG LNGDFNLTLL QVPQVSTSQY SHRSPIEDL LFNKVTIADP GYMQGYDDCM KQGPPSARDL ICAQYVAGYK VLPPLYDPNM EGAYTSSLLG SIAGAGWTAG L SSFAAIPF AQSIFYRMNG IGITQQVLSE NQKLIANKFN QALGAMQTGF TTTNLAFSKV QDAVNANAQA LSKLASELSN TF GAISSSI SDILKRLDPP EQEAQIDRLI NGRLTSLNAF VAQQLVRSET AARSAQLASD KVNECVKSQS KRNGFCGSGT HIV SFVINA PNGFYFFHVG YVPTNHVNVT AAYGLCNTDT PPRCIAPIDG YFVLNNTTTR DVVDQWYYTG SSFFNPEPIT MANA RYVSQ DVKFENLTNQ LPPPLLNNQT DLDFKEELEE FFKNVSSQGP NFQEISKINT TLLDLSTEMK VLNEVVKQLN ESYID LKEL GNYSY

UniProtKB: Spike glycoprotein

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Macromolecule #2: JC57-11 Fab heavy chain

MacromoleculeName: JC57-11 Fab heavy chain / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Macaca (macaques)
Molecular weightTheoretical: 14.167835 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
EVQLLESGPG VVRPSETLSL SCAVSGGSIS DSYRWSWIRQ PPGKGLEWVG YIFATGTTTN YNPSLKSRVT ISKDTSKNQF SLKLSSVTA ADTAVYYCAR EPFKYCSGGV CYAHKDNSLD VWGQGVLVTV SS

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Macromolecule #3: JC57-11 Fab light chain

MacromoleculeName: JC57-11 Fab light chain / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Macaca (macaques)
Molecular weightTheoretical: 11.26345 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
EIVMTQSPAT LSLSPGERAT LSCRASQSVS SNLAWYQQKP GQAPRLLIHS ASSRATGIPD RFSGSGSGTE FSLTISSLEA EDVGVYHCY QHSSGYTFGP GTKLDIK

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Macromolecule #7: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 7 / Number of copies: 18 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

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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
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: DIFFRACTION / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.5 µm
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 80.5 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.0 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 57821
FSC plot (resolution estimation)

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