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- EMDB-36672: Cryo-EM structure of the N-terminal domain of Omicron BA.1 in com... -

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Basic information

Entry
Database: EMDB / ID: EMD-36672
TitleCryo-EM structure of the N-terminal domain of Omicron BA.1 in complex with nanobody N235 and S2L20 Fab
Map data
Sample
  • Complex: the N-terminal domain of Omicron BA.1 in complex with nanobody N235 and S2L20 Fab
    • Protein or peptide: nanobody N235
    • Protein or peptide: S2L20 light chain
    • Protein or peptide: S2L20 heavy chain
    • Protein or peptide: Spike protein S2'
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
Keywordscomplex / VIRAL PROTEIN/IMMUNE SYSTEM / 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 / 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 / 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 speciesVicugna pacos (alpaca) / Homo sapiens (human) / Severe acute respiratory syndrome coronavirus 2
Methodsingle particle reconstruction / cryo EM / Resolution: 2.81 Å
AuthorsLiu B / Liu HH / Han P / Qi JX
Funding support China, 1 items
OrganizationGrant numberCountry
National Science Foundation (NSF, China)82225021 China
CitationJournal: Signal Transduct Target Ther / Year: 2024
Title: Enhanced potency of an IgM-like nanobody targeting conserved epitope in SARS-CoV-2 spike N-terminal domain.
Authors: Bo Liu / Honghui Liu / Pu Han / Xiaoyun Wang / Chunmei Wang / Xinxin Yan / Wenwen Lei / Ke Xu / Jianjie Zhou / Jianxun Qi / Ruiwen Fan / Guizhen Wu / Wen-Xia Tian / George F Gao / Qihui Wang /
Abstract: Almost all the neutralizing antibodies targeting the receptor-binding domain (RBD) of spike (S) protein show weakened or lost efficacy against severe acute respiratory syndrome coronavirus 2 (SARS- ...Almost all the neutralizing antibodies targeting the receptor-binding domain (RBD) of spike (S) protein show weakened or lost efficacy against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged or emerging variants, such as Omicron and its sub-variants. This suggests that highly conserved epitopes are crucial for the development of neutralizing antibodies. Here, we present one nanobody, N235, displaying broad neutralization against the SARS-CoV-2 prototype and multiple variants, including the newly emerged Omicron and its sub-variants. Cryo-electron microscopy demonstrates N235 binds a novel, conserved, cryptic epitope in the N-terminal domain (NTD) of the S protein, which interferes with the RBD in the neighboring S protein. The neutralization mechanism interpreted via flow cytometry and Western blot shows that N235 appears to induce the S1 subunit shedding from the trimeric S complex. Furthermore, a nano-IgM construct (MN235), engineered by fusing N235 with the human IgM Fc region, displays prevention via inducing S1 shedding and cross-linking virus particles. Compared to N235, MN235 exhibits varied enhancement in neutralization against pseudotyped and authentic viruses in vitro. The intranasal administration of MN235 in low doses can effectively prevent the infection of Omicron sub-variant BA.1 and XBB in vivo, suggesting that it can be developed as a promising prophylactic antibody to cope with the ongoing and future infection.
History
DepositionJun 28, 2023-
Header (metadata) releaseMay 22, 2024-
Map releaseMay 22, 2024-
UpdateMay 22, 2024-
Current statusMay 22, 2024Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_36672.png

Downloads & links

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Map

FileDownload / File: emd_36672.map.gz / Format: CCP4 / Size: 512 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.54 Å
Density
Contour LevelBy AUTHOR: 0.16
Minimum - Maximum-0.31099477 - 0.7205311
Average (Standard dev.)-0.0016378993 (±0.014865705)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions512512512
Spacing512512512
CellA=B=C: 276.48 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_36672_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_36672_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 N-terminal domain of Omicron BA.1 in complex with nanobody N2...

EntireName: the N-terminal domain of Omicron BA.1 in complex with nanobody N235 and S2L20 Fab
Components
  • Complex: the N-terminal domain of Omicron BA.1 in complex with nanobody N235 and S2L20 Fab
    • Protein or peptide: nanobody N235
    • Protein or peptide: S2L20 light chain
    • Protein or peptide: S2L20 heavy chain
    • Protein or peptide: Spike protein S2'
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: the N-terminal domain of Omicron BA.1 in complex with nanobody N2...

SupramoleculeName: the N-terminal domain of Omicron BA.1 in complex with nanobody N235 and S2L20 Fab
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4
Source (natural)Organism: Vicugna pacos (alpaca)

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Macromolecule #1: nanobody N235

MacromoleculeName: nanobody N235 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Vicugna pacos (alpaca)
Molecular weightTheoretical: 13.970428 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
QVQLQESGGG LVQPGGSLRL SCAASGLIIS RYDMSWYRQA PGKERELVAT TPIPAARPQY ADSVKGRFTI SRDNAKNTVS LQMNSLKPE DTAVYYCNLG PESQDHNYNY WGQGTQVTVS SHHHHHH

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Macromolecule #2: S2L20 light chain

MacromoleculeName: S2L20 light chain / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 26.017973 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: METDTLLLWV LLLWVPGSTG DVIWMTQSPS SLSASVGDRV TITCQASQDI RFYLNWYQQK PGKAPKLLIS DASNMETGVP SRFSGSGSG TDFTFTISSL QPEDIATYYC QQYDNLPFTF GPGTKVDFKR TVAAPSVFIF PPSDEQLKSG TASVVCLLNN F YPREAKVQ ...String:
METDTLLLWV LLLWVPGSTG DVIWMTQSPS SLSASVGDRV TITCQASQDI RFYLNWYQQK PGKAPKLLIS DASNMETGVP SRFSGSGSG TDFTFTISSL QPEDIATYYC QQYDNLPFTF GPGTKVDFKR TVAAPSVFIF PPSDEQLKSG TASVVCLLNN F YPREAKVQ WKVDNALQSG NSQESVTEQD SKDSTYSLSS TLTLSKADYE KHKVYACEVT HQGLSSPVTK SFNRGECS

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Macromolecule #3: S2L20 heavy chain

MacromoleculeName: S2L20 heavy chain / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 52.041504 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: METDTLLLWV LLLWVPGSTG DEVQLVESGG GVVQPGGSLR LSCAASGFTF NSYGMHWVRQ APGKGLEWVA FIRYDGGNKY YADSVKGRF TISRDNSKNT LYLQMKSLRA EDTAVYYCAN LKDSRYSGSY YDYWGQGTLV TVSSASTKGP SVFPLAPSSK S TSGGTAAL ...String:
METDTLLLWV LLLWVPGSTG DEVQLVESGG GVVQPGGSLR LSCAASGFTF NSYGMHWVRQ APGKGLEWVA FIRYDGGNKY YADSVKGRF TISRDNSKNT LYLQMKSLRA EDTAVYYCAN LKDSRYSGSY YDYWGQGTLV TVSSASTKGP SVFPLAPSSK S TSGGTAAL GCLVKDYFPE PVTVSWNSGA LTSGVHTFPA VLQSSGLYSL SSVVTVPSSS LGTQTYICNV NHKPSNTKVD KR VEPKSCD KTHTCPPCPA PELLGGPSVF LFPPKPKDTL MISRTPEVTC VVVDVSHEDP EVKFNWYVDG VEVHNAKTKP REE QYNSTY RVVSVLTVLH QDWLNGKEYK CKVSNKALPA PIEKTISKAK GQPREPQVYT LPPSRDELTK NQVSLTCLVK GFYP SDIAV EWESNGQPEN NYKTTPPVLD SDGSFFLYSK LTVDKSRWQQ GNVFSCSVMH EALHNHYTQK SLSLSPGK

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Macromolecule #4: Spike protein S2'

MacromoleculeName: Spike protein S2' / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Severe acute respiratory syndrome coronavirus 2 / Strain: Omicron/BA.1
Molecular weightTheoretical: 34.076633 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MFVFLVLLPL VSSQCVNLTT RTQLPPAYTN SFTRGVYYPD KVFRSSVLHS TQDLFLPFFS NVTWFHVISG TNGTKRFDNP VLPFNDGVY FASIEKSNII RGWIFGTTLD SKTQSLLIVN NATNVVIKVC EFQFCNDPFL DHKNNKSWME SEFRVYSSAN N CTFEYVSQ ...String:
MFVFLVLLPL VSSQCVNLTT RTQLPPAYTN SFTRGVYYPD KVFRSSVLHS TQDLFLPFFS NVTWFHVISG TNGTKRFDNP VLPFNDGVY FASIEKSNII RGWIFGTTLD SKTQSLLIVN NATNVVIKVC EFQFCNDPFL DHKNNKSWME SEFRVYSSAN N CTFEYVSQ PFLMDLEGKQ GNFKNLREFV FKNIDGYFKI YSKHTPIIVR EPEDLPQGFS ALEPLVDLPI GINITRFQTL LA LHRSYLT PGDSSSGWTA GAAAYYVGYL QPRTFLLKYN ENGTITDAVD CALDPLSETK CTL

UniProtKB: Spike glycoprotein

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Macromolecule #5: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 5 / Number of copies: 5 / 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: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.0 µm
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 60.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: INSILICO MODEL
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.81 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 139757
FSC plot (resolution estimation)

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