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- EMDB-43436: Prefusion stabilized structure of the SARS-CoV-2 fusion machinery -

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Basic information

Entry
Database: EMDB / ID: EMD-43436
TitlePrefusion stabilized structure of the SARS-CoV-2 fusion machinery
Map data
Sample
  • Complex: Prefusion stabilized structure of the SARS-CoV-2 fusion machinery
    • Protein or peptide: Spike protein S2
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
KeywordsSarbecoviruses / Spike glycoprotein / fusion protein / prefusion-stabilized / Seattle Structural Genomics Center for Infectious Disease / SSGCID / viral protein
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 / membrane fusion / Attachment and Entry / positive regulation of viral entry into host cell / receptor-mediated virion attachment to host cell / receptor ligand activity / host cell surface receptor binding / symbiont-mediated suppression of host innate immune response / 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 / Coronavirus spike glycoprotein S1, C-terminal / Coronavirus spike glycoprotein S1, C-terminal / Spike glycoprotein, betacoronavirus / Spike glycoprotein, N-terminal domain superfamily / Betacoronavirus spike (S) glycoprotein S1 subunit N-terminal (NTD) domain profile. / Betacoronavirus spike (S) glycoprotein S1 subunit C-terminal (CTD) domain profile. / 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, SARS-CoV-2 / Spike (S) protein S1 subunit, N-terminal domain, SARS-CoV-like / Coronavirus spike glycoprotein S1, C-terminal / Coronavirus spike glycoprotein S1, C-terminal / Spike glycoprotein, betacoronavirus / Spike glycoprotein, N-terminal domain superfamily / Betacoronavirus spike (S) glycoprotein S1 subunit N-terminal (NTD) domain profile. / Betacoronavirus spike (S) glycoprotein S1 subunit C-terminal (CTD) domain profile. / Spike (S) protein S1 subunit, receptor-binding domain, betacoronavirus / Spike S1 subunit, receptor binding domain superfamily, betacoronavirus / Spike glycoprotein S1, N-terminal domain, betacoronavirus-like / Betacoronavirus-like spike glycoprotein S1, N-terminal / Betacoronavirus spike glycoprotein S1, receptor binding / Spike glycoprotein S2, coronavirus, heptad repeat 1 / Spike glycoprotein S2, coronavirus, heptad repeat 2 / Coronavirus spike (S) glycoprotein S2 subunit heptad repeat 1 (HR1) region profile. / Coronavirus spike (S) glycoprotein S2 subunit heptad repeat 2 (HR2) region profile. / Spike glycoprotein S2 superfamily, coronavirus / Spike glycoprotein S2, coronavirus / Coronavirus spike glycoprotein S2
Similarity search - Domain/homology
Biological speciesSarbecovirus sp. / Sarbecovirus
Methodsingle particle reconstruction / cryo EM / Resolution: 3.5 Å
AuthorsLee J / Veesler D / Seattle Structural Genomics Center for Infectious Disease (SSGCID)
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)AI158186 United States
CitationJournal: Nat Commun / Year: 2024
Title: A broadly generalizable stabilization strategy for sarbecovirus fusion machinery vaccines.
Authors: Jimin Lee / Cameron Stewart / Alexandra Schäfer / Elizabeth M Leaf / Young-Jun Park / Daniel Asarnow / John M Powers / Catherine Treichel / Kaitlin R Sprouse / Davide Corti / Ralph Baric / ...Authors: Jimin Lee / Cameron Stewart / Alexandra Schäfer / Elizabeth M Leaf / Young-Jun Park / Daniel Asarnow / John M Powers / Catherine Treichel / Kaitlin R Sprouse / Davide Corti / Ralph Baric / Neil P King / David Veesler /
Abstract: Evolution of SARS-CoV-2 alters the antigenicity of the immunodominant spike (S) receptor-binding domain and N-terminal domain, undermining the efficacy of vaccines and antibody therapies. To overcome ...Evolution of SARS-CoV-2 alters the antigenicity of the immunodominant spike (S) receptor-binding domain and N-terminal domain, undermining the efficacy of vaccines and antibody therapies. To overcome this challenge, we set out to develop a vaccine focusing antibody responses on the highly conserved but metastable S subunit, which folds as a spring-loaded fusion machinery. We describe a strategy for prefusion-stabilization and high yield recombinant production of SARS-CoV-2 S trimers with native structure and antigenicity. We demonstrate that our design strategy is broadly generalizable to sarbecoviruses, as exemplified with the SARS-CoV-1 (clade 1a) and PRD-0038 (clade 3) S subunits. Immunization of mice with a prefusion-stabilized SARS-CoV-2 S trimer elicits broadly reactive sarbecovirus antibodies and neutralizing antibody titers of comparable magnitude against Wuhan-Hu-1 and the immune evasive XBB.1.5 variant. Vaccinated mice were protected from weight loss and disease upon challenge with XBB.1.5, providing proof-of-principle for fusion machinery sarbecovirus vaccines.
History
DepositionJan 18, 2024-
Header (metadata) releaseJul 24, 2024-
Map releaseJul 24, 2024-
UpdateOct 23, 2024-
Current statusOct 23, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_43436.png

Downloads & links

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Map

FileDownload / File: emd_43436.map.gz / Format: CCP4 / Size: 163.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
1 Å/pix.
x 350 pix.
= 350. Å		1 Å/pix.
x 350 pix.
= 350. Å		1 Å/pix.
x 350 pix.
= 350. Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1 Å
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Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.5
Minimum - Maximum-3.8525624 - 5.650377
Average (Standard dev.)-0.001228925 (±0.079555206)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions350350350
Spacing350350350
CellA=B=C: 350.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: #1

Fileemd_43436_additional_1.map
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Half map: #2

Fileemd_43436_half_map_1.map
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Half map: #1

Fileemd_43436_half_map_2.map
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Sample components

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Entire : Prefusion stabilized structure of the SARS-CoV-2 fusion machinery

EntireName: Prefusion stabilized structure of the SARS-CoV-2 fusion machinery
Components
  • Complex: Prefusion stabilized structure of the SARS-CoV-2 fusion machinery
    • Protein or peptide: Spike protein S2
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: Prefusion stabilized structure of the SARS-CoV-2 fusion machinery

SupramoleculeName: Prefusion stabilized structure of the SARS-CoV-2 fusion machinery
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Sarbecovirus sp.

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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: Sarbecovirus
Molecular weightTheoretical: 68.328492 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MGILPSPGMP ALLSLVSLLS VLLMGCVAET GTSVASQSII AYTMSLGAEN SVACSNNSIA IPTNFTISVT TEILPVSMTK TSVDCTMYI CGDSTECSNL LLQYGSFCTQ LNRALTGIAV EQDKNTQEVF AQVKQIYKTP PIKDFGGFNF SQILPDPSKP S KRSFIEDL ...String:
MGILPSPGMP ALLSLVSLLS VLLMGCVAET GTSVASQSII AYTMSLGAEN SVACSNNSIA IPTNFTISVT TEILPVSMTK TSVDCTMYI CGDSTECSNL LLQYGSFCTQ LNRALTGIAV EQDKNTQEVF AQVKQIYKTP PIKDFGGFNF SQILPDPSKP S KRSFIEDL LFNKVTLADA GFIKQYGDCL GDIAARDLIC AQKFNGLTVL PPLLTDEMIA QYTSALLAGT ICSGWTPGAG PP LQIPFPM QMAYRFEGIG VTQNVLYENQ KLIANQFNSA IGKIQDSLSS TPSALGKLQD VVNQNAQALN FLVKQLSSNC GAI SSVLND ILSRLDKPEA EVQIQRLIQC RLQSLQTYVT MMLIRAAEYR ASAMLAATKM SECVLGQSKR VDFCGKGYHL MSFP QSAPH GVVFLHVTYV PAQEKNFTTA PAICHDGKAH FPREGVFVSN GTHWFVTQRN FYEPQIITTD NTFVSGNCDV VIGIV NNTV YDPLQPELDS FKEELDKYFK NHTSPDVDLG DISGINASVV NIQKEIDRLN EVAKNLNESL IDLQELGKYE QGSGYI PEA PRDGQAYVRK DGEWVLLSTF LGRSLEVLFQ GPGSGGLNDI FEAQKIEWHE GSGHHHHHHH H

UniProtKB: Spike glycoprotein

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Macromolecule #3: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 3 / Number of copies: 6 / 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: 8
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: 63.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 3.0 µm / Nominal defocus min: 0.2 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 144044
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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