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- EMDB-35740: Cryo-EM structure of SARS-CoV-2 spike protein in complex with dou... -

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Entry
Database: EMDB / ID: EMD-35740
TitleCryo-EM structure of SARS-CoV-2 spike protein in complex with double nAbs 8H12 and 3E2 (local refinement)
Map data
Sample
  • Complex: Cryo-EM structure of SARS-CoV-2 spike protein in complex with double nAbs 3E2 and 1C4
    • Complex: SARS-CoV-2 spike proteinCoronavirus spike protein
      • Protein or peptide: light chain of 3E2
    • Complex: nAbs 8H12 and 3E2
      • Protein or peptide: heavy chain of 3E2
      • Protein or peptide: light chain of 8H12
      • Protein or peptide: heavy chain of 8H12
      • Protein or peptide: Spike protein S1
KeywordsSARS-CoV-2 / Neutralizing antibody / Cryo-EM / VIRAL PROTEIN / VIRAL PROTEIN-IMMUNE SYSTEM complex
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 / 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 / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / virion attachment to host cell / SARS-CoV-2 activates/modulates innate and adaptive immune responses / host cell plasma membrane / virion membrane / membrane / identical protein binding / 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 / Mus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.59 Å
AuthorsSun H / Jiang Y / Zheng Q / Li S / Xia N
Funding support1 items
OrganizationGrant numberCountry
Not funded
CitationJournal: Protein Cell / Year: 2024
Title: Two antibodies show broad, synergistic neutralization against SARS-CoV-2 variants by inducing conformational change within the RBD.
Authors: Hui Sun / Tingting Deng / Yali Zhang / Yanling Lin / Yanan Jiang / Yichao Jiang / Yang Huang / Shuo Song / Lingyan Cui / Tingting Li / Hualong Xiong / Miaolin Lan / Liqin Liu / Yu Li / ...Authors: Hui Sun / Tingting Deng / Yali Zhang / Yanling Lin / Yanan Jiang / Yichao Jiang / Yang Huang / Shuo Song / Lingyan Cui / Tingting Li / Hualong Xiong / Miaolin Lan / Liqin Liu / Yu Li / Qianjiao Fang / Kunyu Yu / Wenling Jiang / Lizhi Zhou / Yuqiong Que / Tianying Zhang / Quan Yuan / Tong Cheng / Zheng Zhang / Hai Yu / Jun Zhang / Wenxin Luo / Shaowei Li / Qingbing Zheng / Ying Gu / Ningshao Xia /
Abstract: Continual evolution of the severe acute respiratory syndrome coronavirus (SARS-CoV-2) virus has allowed for its gradual evasion of neutralizing antibodies (nAbs) produced in response to natural ...Continual evolution of the severe acute respiratory syndrome coronavirus (SARS-CoV-2) virus has allowed for its gradual evasion of neutralizing antibodies (nAbs) produced in response to natural infection or vaccination. The rapid nature of these changes has incited a need for the development of superior broad nAbs (bnAbs) and/or the rational design of an antibody cocktail that can protect against the mutated virus strain. Here, we report two angiotensin-converting enzyme 2 competing nAbs-8H12 and 3E2-with synergistic neutralization but evaded by some Omicron subvariants. Cryo-electron microscopy reveals the two nAbs synergistic neutralizing virus through a rigorous pairing permitted by rearrangement of the 472-489 loop in the receptor-binding domain to avoid steric clashing. Bispecific antibodies based on these two nAbs tremendously extend the neutralizing breadth and restore neutralization against recent variants including currently dominant XBB.1.5. Together, these findings expand our understanding of the potential strategies for the neutralization of SARS-CoV-2 variants toward the design of broad-acting antibody therapeutics and vaccines.
History
DepositionMar 26, 2023-
Header (metadata) releaseAug 16, 2023-
Map releaseAug 16, 2023-
UpdateFeb 14, 2024-
Current statusFeb 14, 2024Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_35740.png

Downloads & links

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Map

FileDownload / File: emd_35740.map.gz / Format: CCP4 / Size: 729 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.778 Å
Density
Contour LevelBy AUTHOR: 0.13
Minimum - Maximum-0.87365144 - 1.3678528
Average (Standard dev.)-0.00014400504 (±0.013493968)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions576576576
Spacing576576576
CellA=B=C: 448.128 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_35740_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_35740_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 : Cryo-EM structure of SARS-CoV-2 spike protein in complex with dou...

EntireName: Cryo-EM structure of SARS-CoV-2 spike protein in complex with double nAbs 3E2 and 1C4
Components
  • Complex: Cryo-EM structure of SARS-CoV-2 spike protein in complex with double nAbs 3E2 and 1C4
    • Complex: SARS-CoV-2 spike proteinCoronavirus spike protein
      • Protein or peptide: light chain of 3E2
    • Complex: nAbs 8H12 and 3E2
      • Protein or peptide: heavy chain of 3E2
      • Protein or peptide: light chain of 8H12
      • Protein or peptide: heavy chain of 8H12
      • Protein or peptide: Spike protein S1

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Supramolecule #1: Cryo-EM structure of SARS-CoV-2 spike protein in complex with dou...

SupramoleculeName: Cryo-EM structure of SARS-CoV-2 spike protein in complex with double nAbs 3E2 and 1C4
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all

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Supramolecule #2: SARS-CoV-2 spike protein

SupramoleculeName: SARS-CoV-2 spike protein / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1
Source (natural)Organism: Severe acute respiratory syndrome coronavirus 2

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Supramolecule #3: nAbs 8H12 and 3E2

SupramoleculeName: nAbs 8H12 and 3E2 / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #2-#5
Source (natural)Organism: Mus musculus (house mouse)

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Macromolecule #1: light chain of 3E2

MacromoleculeName: light chain of 3E2 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 11.203357 KDa
SequenceString:
QIVLTQSPAI MSASLGEEIT LTCSVSSSVS DMHWYQQKSG TSPKVFIYST SNLASGVPSR FSGSGSGTFY SLTISSVEAE DAAYYYCHQ WSSWTFGGGT KLEIK

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Macromolecule #2: heavy chain of 3E2

MacromoleculeName: heavy chain of 3E2 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 13.105676 KDa
SequenceString:
EVMLVESGGG VVKPGGSLKL SCAASGFSFS TYAMSWIRQT PEKSLEWVAA ISSGGTNTYY PGSVKGRFTI SRDKAMNTLY LQLSSLRSE DTAMYYCVRH SGNYVDSVMD YWGQGTSVTV SS

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Macromolecule #3: light chain of 8H12

MacromoleculeName: light chain of 8H12 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 11.945558 KDa
SequenceString:
DIVMTQFQKF MSTSVGDRVS ITCKASQNVR TAVAWYQQKP GQSPKAMIYL ASNRHRGVPD RFTGSGCGTD FTLTISNVQC EDLADYFCL QHRNYPLTFG GGTKLEIK

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Macromolecule #4: heavy chain of 8H12

MacromoleculeName: heavy chain of 8H12 / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 13.240784 KDa
SequenceString:
EVKLEESGGG LVQPGGSMKL SCAASGFTFS DAWMDWVRQS PEKGLEWVAQ IRRKANNHAT YYAESVKGRF TISRDDSKSS VYLQMNSLR AEDTGIYYCI RGMTYAMDFW GQGTSVTVSS

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Macromolecule #5: Spike protein S1

MacromoleculeName: Spike protein S1 / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Severe acute respiratory syndrome coronavirus 2
Molecular weightTheoretical: 22.930721 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: ESIVRFPNIT NLCPFGEVFN ATRFASVYAW NRKRISNCVA DYSVLYNSAS FSTFKCYGVS PTKLNDLCFT NVYADSFVIR GDEVRQIAP GQTGKIADYN YKLPDDFTGC VIAWNSNNLD SKVGGNYNYL YRLFRKSNLK PFERDISTEI YQAGSTPCNG V EGFNCYFP ...String:
ESIVRFPNIT NLCPFGEVFN ATRFASVYAW NRKRISNCVA DYSVLYNSAS FSTFKCYGVS PTKLNDLCFT NVYADSFVIR GDEVRQIAP GQTGKIADYN YKLPDDFTGC VIAWNSNNLD SKVGGNYNYL YRLFRKSNLK PFERDISTEI YQAGSTPCNG V EGFNCYFP LQSYGFQPTN GVGYQPYRVV VLSFELLHAP ATVCGP

UniProtKB: Spike glycoprotein

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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: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TECNAI F30
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2.4 µm / Nominal defocus min: 1.0 µm
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 60.0 e/Å2
Experimental equipment
Model: Tecnai F30 / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.59 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 217835

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