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- EMDB-30573: A proof of concept for neutralizing antibody-guided vaccine desig... -

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Basic information

Entry
Database: EMDB / ID: EMD-30573
TitleA proof of concept for neutralizing antibody-guided vaccine design against SARS-CoV-2
Map data
Sample
  • Complex: FC05 Fab binds to SARS-CoV-2 Spike
    • Complex: Spike protein S1
      • Protein or peptide: Spike glycoprotein S1
    • Complex: FC05 Fab
      • Protein or peptide: Light chain of FC05 Fab
      • Protein or peptide: Heavy chain of FC05 Fab
Function / homology
Function and homology information


Maturation of spike protein / viral translation / Translation of Structural Proteins / Virion Assembly and Release / host cell surface / host extracellular space / suppression by virus of host tetherin activity / Induction of Cell-Cell Fusion / structural constituent of virion / entry receptor-mediated virion attachment to host cell ...Maturation of spike protein / viral translation / Translation of Structural Proteins / Virion Assembly and Release / host cell surface / host extracellular space / suppression by virus of host tetherin activity / Induction of Cell-Cell Fusion / structural constituent of virion / entry receptor-mediated virion attachment to host cell / host cell endoplasmic reticulum-Golgi intermediate compartment membrane / receptor-mediated endocytosis of virus by host cell / Attachment and Entry / membrane fusion / symbiont-mediated suppression of host innate immune response / positive regulation of viral entry into host cell / receptor-mediated virion attachment to host cell / receptor ligand activity / host cell surface receptor binding / fusion of virus membrane with host plasma membrane / fusion of virus membrane with host endosome membrane / viral envelope / virion attachment to host cell / SARS-CoV-2 activates/modulates innate and adaptive immune responses / host cell plasma membrane / virion membrane / identical protein binding / membrane / plasma membrane
Similarity search - Function
Spike (S) protein S1 subunit, receptor-binding domain, SARS-CoV-2 / Spike (S) protein S1 subunit, N-terminal domain, SARS-CoV-like / 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 ...Spike (S) protein S1 subunit, receptor-binding domain, SARS-CoV-2 / Spike (S) protein S1 subunit, N-terminal domain, SARS-CoV-like / 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 speciesSevere acute respiratory syndrome coronavirus 2 / Homo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.9 Å
AuthorsCao L / Wang X
CitationJournal: Natl Sci Rev / Year: 2021
Title: A proof of concept for neutralizing antibody-guided vaccine design against SARS-CoV-2.
Authors: Li Zhang / Lei Cao / Xing-Su Gao / Bin-Yang Zheng / Yong-Qiang Deng / Jing-Xin Li / Rui Feng / Qian Bian / Xi-Ling Guo / Nan Wang / Hong-Ying Qiu / Lei Wang / Zhen Cui / Qing Ye / Geng Chen ...Authors: Li Zhang / Lei Cao / Xing-Su Gao / Bin-Yang Zheng / Yong-Qiang Deng / Jing-Xin Li / Rui Feng / Qian Bian / Xi-Ling Guo / Nan Wang / Hong-Ying Qiu / Lei Wang / Zhen Cui / Qing Ye / Geng Chen / Kui-Kui Lu / Yin Chen / Yu-Tao Chen / Hong-Xing Pan / Jiaping Yu / Wenrong Yao / Bao-Li Zhu / Jianping Chen / Yong Liu / Cheng-Feng Qin / Xiangxi Wang / Feng-Cai Zhu /
Abstract: Mutations and transient conformational movements of the receptor binding domain (RBD) that make neutralizing epitopes momentarily unavailable present immune escape routes for severe acute respiratory ...Mutations and transient conformational movements of the receptor binding domain (RBD) that make neutralizing epitopes momentarily unavailable present immune escape routes for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To mitigate viral escape, we developed a cocktail of neutralizing antibodies (NAbs) targeting epitopes located on different domains of spike (S) protein. Screening of a library of monoclonal antibodies generated from peripheral blood mononuclear cells of COVID-19 convalescent patients yielded potent NAbs, targeting the N-terminal domain (NTD) and RBD domain of S, effective at concentrations. Remarkably, a combination of RBD-targeting NAbs and NTD-binding NAbs, FC05, enhanced the neutralization potency in cell-based assays and an animal model. Results of competitive surface plasmon resonance assays and cryo-electron microscopy (cryo-EM) structures of antigen-binding fragments bound to S unveil determinants of immunogenicity. Combinations of immunogens, identified in the NTD and RBD of S, when immunized in rabbits and macaques, elicited potent protective immune responses against SARS-CoV-2. More importantly, two immunizations of this combination of NTD and RBD immunogens provided complete protection in macaques against a SARS-CoV-2 challenge, without observable antibody-dependent enhancement of infection. These results provide a proof of concept for neutralization-based immunogen design targeting SARS-CoV-2 NTD and RBD.
History
DepositionSep 23, 2020-
Header (metadata) releaseApr 7, 2021-
Map releaseApr 7, 2021-
UpdateFeb 23, 2022-
Current statusFeb 23, 2022Processing site: PDBj / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.016
  • Imaged by UCSF Chimera
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  • Surface view colored by height
  • Surface level: 0.016
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7d4g
  • Surface level: 0.016
  • Imaged by UCSF Chimera
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  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-7d4g
  • Imaged by Jmol
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_30573.png

Downloads & links

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Map

FileDownload / File: emd_30573.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.04 Å
Density
Contour LevelBy AUTHOR: 0.016 / Movie #1: 0.016
Minimum - Maximum-0.095674 - 0.1562097
Average (Standard dev.)-4.646387e-05 (±0.0016868974)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 332.8 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.041.041.04
M x/y/z320320320
origin x/y/z0.0000.0000.000
length x/y/z332.800332.800332.800
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ160160160
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS320320320
D min/max/mean-0.0960.156-0.000

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Supplemental data

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Sample components

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Entire : FC05 Fab binds to SARS-CoV-2 Spike

EntireName: FC05 Fab binds to SARS-CoV-2 Spike
Components
  • Complex: FC05 Fab binds to SARS-CoV-2 Spike
    • Complex: Spike protein S1
      • Protein or peptide: Spike glycoprotein S1
    • Complex: FC05 Fab
      • Protein or peptide: Light chain of FC05 Fab
      • Protein or peptide: Heavy chain of FC05 Fab

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Supramolecule #1: FC05 Fab binds to SARS-CoV-2 Spike

SupramoleculeName: FC05 Fab binds to SARS-CoV-2 Spike / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Severe acute respiratory syndrome coronavirus 2
Recombinant expressionOrganism: Homo sapiens (human) / Recombinant cell: HEK293T

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Supramolecule #2: Spike protein S1

SupramoleculeName: Spike protein S1 / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human) / Recombinant cell: HEK293T

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Supramolecule #3: FC05 Fab

SupramoleculeName: FC05 Fab / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #2-#3

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Macromolecule #1: Spike glycoprotein S1

MacromoleculeName: Spike glycoprotein S1 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Severe acute respiratory syndrome coronavirus 2
Molecular weightTheoretical: 31.663637 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: SQCVNLTTRT QLPPAYTNSF TRGVYYPDKV FRSSVLHSTQ DLFLPFFSNV TWFHAIHVSG TNGTKRFDNP VLPFNDGVYF ASTEKSNII RGWIFGTTLD SKTQSLLIVN NATNVVIKVC EFQFCNDPFL GVYYHKNNKS WMESEFRVYS SANNCTFEYV S QPFLMDLE ...String:
SQCVNLTTRT QLPPAYTNSF TRGVYYPDKV FRSSVLHSTQ DLFLPFFSNV TWFHAIHVSG TNGTKRFDNP VLPFNDGVYF ASTEKSNII RGWIFGTTLD SKTQSLLIVN NATNVVIKVC EFQFCNDPFL GVYYHKNNKS WMESEFRVYS SANNCTFEYV S QPFLMDLE GKQGNFKNLR EFVFKNIDGY FKIYSKHTPI NLVRDLPQGF SALEPLVDLP IGINITRFQT LLALHRSYLT PG DSSSGWT AGAAAYYVGY LQPRTFLLKY NENGTITDAV D

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Macromolecule #2: Light chain of FC05 Fab

MacromoleculeName: Light chain of FC05 Fab / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 11.34548 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
QSVLTQAPSV SGAPGQKVTI SCSGSSSNIG NNYVSWYQQL PGTAPKLLIY DNNKRPSGIP DRFSGSKSGT SATLGITGLQ TGDEADYYC GTWDSSLSAV VFGGGTKLTV L

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Macromolecule #3: Heavy chain of FC05 Fab

MacromoleculeName: Heavy chain of FC05 Fab / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 13.463899 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
EVQLLEQSGA EVKKPGASVR VSCKVSGYTL PEVAMHWVRQ APGKGLEWMG GFDPEDGETM YAQKFQGRVT MTEDTSTDTA YMELSSLRS EDTAVYYCAT TTPFSSSYWF DPWGQGTLVT VSS

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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 K2 QUANTUM (4k 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
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.9 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 450378
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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