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- EMDB-27098: Cryo-EM structure of the SARS-CoV-2 HR1HR2 fusion core complex wi... -

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Basic information

Entry
Database: EMDB / ID: EMD-27098
TitleCryo-EM structure of the SARS-CoV-2 HR1HR2 fusion core complex with extended HR2
Map data
Sample
  • Complex: SARS-CoV-2 HR1HR2 complex
    • Protein or peptide: Scaffolded Spike protein S2' HR1
    • Protein or peptide: Spike protein S2' HR2
Function / homology
Function and homology information


oxidoreductase activity, acting on metal ions / ferric iron binding / 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 ...oxidoreductase activity, acting on metal ions / ferric iron binding / 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 / 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
Dps protein family signature 2. / DNA-binding protein Dps, conserved site / DNA-binding protein Dps / Ferritin/DPS protein domain / Ferritin-like domain / Ferritin-like / Ferritin-like superfamily / 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. ...Dps protein family signature 2. / DNA-binding protein Dps, conserved site / DNA-binding protein Dps / Ferritin/DPS protein domain / Ferritin-like domain / Ferritin-like / Ferritin-like superfamily / 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
Ferritin, Dps family protein / Spike glycoprotein
Similarity search - Component
Biological speciesSevere acute respiratory syndrome coronavirus 2
Methodsingle particle reconstruction / cryo EM / Resolution: 2.22 Å
AuthorsYang K / Brunger AT
Funding support United States, 1 items
OrganizationGrant numberCountry
Howard Hughes Medical Institute (HHMI) United States
CitationJournal: Proc Natl Acad Sci U S A / Year: 2022
Title: Nanomolar inhibition of SARS-CoV-2 infection by an unmodified peptide targeting the prehairpin intermediate of the spike protein.
Authors: Kailu Yang / Chuchu Wang / Alex J B Kreutzberger / Ravi Ojha / Suvi Kuivanen / Sergio Couoh-Cardel / Serena Muratcioglu / Timothy J Eisen / K Ian White / Richard G Held / Subu Subramanian / ...Authors: Kailu Yang / Chuchu Wang / Alex J B Kreutzberger / Ravi Ojha / Suvi Kuivanen / Sergio Couoh-Cardel / Serena Muratcioglu / Timothy J Eisen / K Ian White / Richard G Held / Subu Subramanian / Kendra Marcus / Richard A Pfuetzner / Luis Esquivies / Catherine A Doyle / John Kuriyan / Olli Vapalahti / Giuseppe Balistreri / Tom Kirchhausen / Axel T Brunger /
Abstract: Variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) challenge currently available coronavirus disease 2019 vaccines and monoclonal antibody therapies through epitope change on ...Variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) challenge currently available coronavirus disease 2019 vaccines and monoclonal antibody therapies through epitope change on the receptor binding domain of the viral spike glycoprotein. Hence, there is a specific urgent need for alternative antivirals that target processes less likely to be affected by mutation, such as the membrane fusion step of viral entry into the host cell. One such antiviral class includes peptide inhibitors, which block formation of the so-called heptad repeat 1 and 2 (HR1HR2) six-helix bundle of the SARS-CoV-2 spike (S) protein and thus interfere with viral membrane fusion. We performed structural studies of the HR1HR2 bundle, revealing an extended, well-folded N-terminal region of HR2 that interacts with the HR1 triple helix. Based on this structure, we designed an extended HR2 peptide that achieves single-digit nanomolar inhibition of SARS-CoV-2 in cell-based and virus-based assays without the need for modifications such as lipidation or chemical stapling. The peptide also strongly inhibits all major SARS-CoV-2 variants to date. This extended peptide is ∼100-fold more potent than all previously published short, unmodified HR2 peptides, and it has a very long inhibition lifetime after washout in virus infection assays, suggesting that it targets a prehairpin intermediate of the SARS-CoV-2 S protein. Together, these results suggest that regions outside the HR2 helical region may offer new opportunities for potent peptide-derived therapeutics for SARS-CoV-2 and its variants, and even more distantly related viruses, and provide further support for the prehairpin intermediate of the S protein.
History
DepositionMay 24, 2022-
Header (metadata) releaseSep 7, 2022-
Map releaseSep 7, 2022-
UpdateMar 22, 2023-
Current statusMar 22, 2023Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_27098.png

Downloads & links

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Map

FileDownload / File: emd_27098.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.81625 Å
Density
Contour LevelBy AUTHOR: 0.05
Minimum - Maximum-0.0017756171 - 1.5826159
Average (Standard dev.)0.00065225206 (±0.018652081)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 208.96 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_27098_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_27098_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
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Histogram

Histogram (log scale)

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Sample components

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Entire : SARS-CoV-2 HR1HR2 complex

EntireName: SARS-CoV-2 HR1HR2 complex
Components
  • Complex: SARS-CoV-2 HR1HR2 complex
    • Protein or peptide: Scaffolded Spike protein S2' HR1
    • Protein or peptide: Spike protein S2' HR2

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Supramolecule #1: SARS-CoV-2 HR1HR2 complex

SupramoleculeName: SARS-CoV-2 HR1HR2 complex / type: complex / ID: 1 / Chimera: Yes / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Severe acute respiratory syndrome coronavirus 2
Molecular weightTheoretical: 40 KDa

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Macromolecule #1: Scaffolded Spike protein S2' HR1

MacromoleculeName: Scaffolded Spike protein S2' HR1 / type: protein_or_peptide / ID: 1 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Severe acute respiratory syndrome coronavirus 2
Molecular weightTheoretical: 28.759055 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MSHHHHHHGS QTLLRNFGNV YDNPVLLDRS VTAPVTEGFN VVLASFQALY LQYQKHHFVV EGSEFYSLHE FFNESYNQVQ DHIHEIGER LDGLGGVPVA TFSKLAELTC FEQESEGVYS SRQMVENDLA AEQAIIGVIR RQAAQAESLG DRGTRYLYEK I LLKTEERA ...String:
MSHHHHHHGS QTLLRNFGNV YDNPVLLDRS VTAPVTEGFN VVLASFQALY LQYQKHHFVV EGSEFYSLHE FFNESYNQVQ DHIHEIGER LDGLGGVPVA TFSKLAELTC FEQESEGVYS SRQMVENDLA AEQAIIGVIR RQAAQAESLG DRGTRYLYEK I LLKTEERA YHLSHFLAKD SLTLGFAYEN QKLIANQFNS AIGKIQDSLS STASALGKLQ DVVNQNAQAL NTLVKQLSSN FG AISSVLN DILSRLDKVE

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Macromolecule #2: Spike protein S2' HR2

MacromoleculeName: Spike protein S2' HR2 / type: protein_or_peptide / ID: 2 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Severe acute respiratory syndrome coronavirus 2
Molecular weightTheoretical: 4.935439 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
KNHTSPDVDL GDISGINASV VNIQKEIDRL NEVAKNLNES LIDLQ

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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 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: 0.3 µm
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 47.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.22 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 751443

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