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- EMDB-35934: Cryo-EM reconstruction of SARS-CoV2 Omicron BA.5 spike in complex... -

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Basic information

Entry
Database: EMDB / ID: EMD-35934
TitleCryo-EM reconstruction of SARS-CoV2 Omicron BA.5 spike in complex with 8-9D Fabs
Map data
Sample
  • Complex: Severe acute respiratory syndrome coronavirus 2 Omicron BA.5 spike bound 8-9D Fab
    • Complex: 8-9D Fab variable region
      • Protein or peptide: 8-9D heavy chain
      • Protein or peptide: 8-9D light chain
    • Complex: SARS-CoV2 Omicron BA.5 spike ectodomain
      • Protein or peptide: Spike protein S2'
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
KeywordsVIRAL 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 / host cell endoplasmic reticulum-Golgi intermediate compartment membrane ...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 / host cell endoplasmic reticulum-Golgi intermediate compartment membrane / entry receptor-mediated virion attachment to host cell / 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 / 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: 3.01 Å
AuthorsXiang Y / Li R
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: Nat Commun / Year: 2023
Title: A lung-selective delivery of mRNA encoding broadly neutralizing antibody against SARS-CoV-2 infection.
Authors: Wanbo Tai / Kai Yang / Yubin Liu / Ruofan Li / Shengyong Feng / Benjie Chai / Xinyu Zhuang / Shaolong Qi / Huicheng Shi / Zhida Liu / Jiaqi Lei / Enhao Ma / Weixiao Wang / Chongyu Tian / ...Authors: Wanbo Tai / Kai Yang / Yubin Liu / Ruofan Li / Shengyong Feng / Benjie Chai / Xinyu Zhuang / Shaolong Qi / Huicheng Shi / Zhida Liu / Jiaqi Lei / Enhao Ma / Weixiao Wang / Chongyu Tian / Ting Le / Jinyong Wang / Yunfeng Chen / Mingyao Tian / Ye Xiang / Guocan Yu / Gong Cheng /
Abstract: The respiratory system, especially the lung, is the key site of pathological injury induced by SARS-CoV-2 infection. Given the low feasibility of targeted delivery of antibodies into the lungs by ...The respiratory system, especially the lung, is the key site of pathological injury induced by SARS-CoV-2 infection. Given the low feasibility of targeted delivery of antibodies into the lungs by intravenous administration and the short half-life period of antibodies in the lungs by intranasal or aerosolized immunization, mRNA encoding broadly neutralizing antibodies with lung-targeting capability can perfectly provide high-titer antibodies in lungs to prevent the SARS-CoV-2 infection. Here, we firstly identify a human monoclonal antibody, 8-9D, with broad neutralizing potency against SARS-CoV-2 variants. The neutralization mechanism of this antibody is explained by the structural characteristics of 8-9D Fabs in complex with the Omicron BA.5 spike. In addition, we evaluate the efficacy of 8-9D using a safe and robust mRNA delivery platform and compare the performance of 8-9D when its mRNA is and is not selectively delivered to the lungs. The lung-selective delivery of the 8-9D mRNA enables the expression of neutralizing antibodies in the lungs which blocks the invasion of the virus, thus effectively protecting female K18-hACE2 transgenic mice from challenge with the Beta or Omicron BA.1 variant. Our work underscores the potential application of lung-selective mRNA antibodies in the prevention and treatment of infections caused by circulating SARS-CoV-2 variants.
History
DepositionApr 13, 2023-
Header (metadata) releaseNov 29, 2023-
Map releaseNov 29, 2023-
UpdateDec 20, 2023-
Current statusDec 20, 2023Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_35934.png

Downloads & links

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Map

FileDownload / File: emd_35934.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.97 Å
Density
Contour LevelBy AUTHOR: 0.2
Minimum - Maximum-0.021450497 - 1.9788045
Average (Standard dev.)0.0013318706 (±0.02399175)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions384384384
Spacing384384384
CellA=B=C: 372.48 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_35934_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_35934_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 : Severe acute respiratory syndrome coronavirus 2 Omicron BA.5 spik...

EntireName: Severe acute respiratory syndrome coronavirus 2 Omicron BA.5 spike bound 8-9D Fab
Components
  • Complex: Severe acute respiratory syndrome coronavirus 2 Omicron BA.5 spike bound 8-9D Fab
    • Complex: 8-9D Fab variable region
      • Protein or peptide: 8-9D heavy chain
      • Protein or peptide: 8-9D light chain
    • Complex: SARS-CoV2 Omicron BA.5 spike ectodomain
      • Protein or peptide: Spike protein S2'
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: Severe acute respiratory syndrome coronavirus 2 Omicron BA.5 spik...

SupramoleculeName: Severe acute respiratory syndrome coronavirus 2 Omicron BA.5 spike bound 8-9D Fab
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Source (natural)Organism: Severe acute respiratory syndrome coronavirus 2
Molecular weightTheoretical: 369 KDa

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Supramolecule #2: 8-9D Fab variable region

SupramoleculeName: 8-9D Fab variable region / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #2-#3
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #3: SARS-CoV2 Omicron BA.5 spike ectodomain

SupramoleculeName: SARS-CoV2 Omicron BA.5 spike ectodomain / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #1

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Macromolecule #1: Spike protein S2'

MacromoleculeName: Spike protein S2' / type: protein_or_peptide / ID: 1 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Severe acute respiratory syndrome coronavirus 2
Molecular weightTheoretical: 123.511086 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: TQSYTNSFTR GVYYPDKVFR SSVLHSTQDL FLPFFSNVTW FHAISGTNGT KRFDNPVLPF NDGVYFASTE KSNIIRGWIF GTTLDSKTQ SLLIVNNATN VVIKVCEFQF CNDPFLDVYY HKNNKSWMES EFRVYSSANN CTFEYVSQPF LMDLEGKQGN F KNLREFVF ...String:
TQSYTNSFTR GVYYPDKVFR SSVLHSTQDL FLPFFSNVTW FHAISGTNGT KRFDNPVLPF NDGVYFASTE KSNIIRGWIF GTTLDSKTQ SLLIVNNATN VVIKVCEFQF CNDPFLDVYY HKNNKSWMES EFRVYSSANN CTFEYVSQPF LMDLEGKQGN F KNLREFVF KNIDGYFKIY SKHTPINLGR DLPQGFSALE PLVDLPIGIN ITRFQTLLAL HRSYLTPGDS SSGWTAGAAA YY VGYLQPR TFLLKYNENG TITDAVDCAL DPLSETKCTL KSFTVEKGIY QTSNFRVQPT ESIVRFPNIT NLCPFDEVFN ATR FASVYA WNRKRISNCV ADYSVLYNFA PFFAFKCYGV SPTKLNDLCF TNVYADSFVI RGNEVSQIAP GQTGNIADYN YKLP DDFTG CVIAWNSNKL DSKVGGNYNY RYRLFRKSNL KPFERDISTE IYQAGNKPCN GVAGVNCYFP LQSYGFRPTY GVGHQ PYRV VVLSFELLHA PATVCGPKKS TNLVKNKCVN FNFNGLTGTG VLTESNKKFL PFQQFGRDIA DTTDAVRDPQ TLEILD ITP CSFGGVSVIT PGTNTSNQVA VLYQGVNCTE VPVAIHADQL TPTWRVYSTG SNVFQTRAGC LIGAEYVNNS YECDIPI GA GICASYQTQT KSHGSASSVA SQSIIAYTMS LGAENSVAYS NNSIAIPTNF TISVTTEILP VSMTKTSVDC TMYICGDS T ECSNLLLQYG SFCTQLKRAL TGIAVEQDKN TQEVFAQVKQ IYKTPPIKYF GGFNFSQILP DPSKPSKRSP IEDLLFNKV TLADAGFIKQ YGDCLGDIAA RDLICAQKFN GLTVLPPLLT DEMIAQYTSA LLAGTITSGW TFGAGPALQI PFPMQMAYRF NGIGVTQNV LYENQKLIAN QFNSAIGKIQ DSLSSTPSAL GKLQDVVNHN AQALNTLVKQ LSSKFGAISS VLNDILSRLD P PEAEVQID RLITGRLQSL QTYVTQQLIR AAEIRASANL AATKMSECVL GQSKRVDFCG KGYHLMSFPQ SAPHGVVFLH VT YVPAQEK NFTTAPAICH DGKAHFPREG VFVSNGTHWF VTQRNFYEPQ IITTDNTFVS GNCDVVIGIV NNTVYDPL

UniProtKB: Spike glycoprotein

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Macromolecule #2: 8-9D heavy chain

MacromoleculeName: 8-9D heavy chain / type: protein_or_peptide / ID: 2 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 12.439867 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
VQLVESGGGL VQPGGSLRLS CAASGLTVSS NYMNWVRQAP GKGLEWVSVF YPGGSTFYAD SVRGRFTISR DNSKNTLYLQ MNSLRAEDT AVYYCARDHS GHALDIWGQG TMVTVS

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Macromolecule #3: 8-9D light chain

MacromoleculeName: 8-9D light chain / type: protein_or_peptide / ID: 3 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 11.729067 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
DIQMTQSPSF LSASVGDRVT ITCRASQGIS SYLAWYQQKP GKAPKLLIYA ASTLQSGVPS RFSGSGSGTE FTLTISSLQP EDFATYYCQ HLNSYPSMYT FGQGTKVDI

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Macromolecule #4: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 4 / Number of copies: 27 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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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: 7.7
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: 50.0 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: 1.5 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

6xey

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.01 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 296568
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementProtocol: FLEXIBLE FIT
Output model

PDB-8j1v:
Cryo-EM structure of SARS-CoV2 Omicron BA.5 spike in complex with 8-9D Fabs

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