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- EMDB-22914: Structure of the SARS-CoV-2 S 6P trimer in complex with the ACE2 ... -

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Basic information

Entry
Database: EMDB / ID: EMD-22914
TitleStructure of the SARS-CoV-2 S 6P trimer in complex with the ACE2 protein decoy, CTC-445.2 (State 2)
Map data
SampleTernary complex of CTC445.2 inhibitor with SARS-CoV-2 S 6P glycoprotin
  • Spike glycoproteinPeplomer
  • (CTC-445.2 inhibitor) x 2
  • SARS-CoV-2 stabilized 6P spike glycoprotein
Biological speciesSevere acute respiratory syndrome coronavirus 2 / Homo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.9 Å
AuthorsBarnes CO / Bjorkman PJ
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)P01-AI13893 United States
CitationJournal: Science / Year: 2020
Title: De novo design of potent and resilient hACE2 decoys to neutralize SARS-CoV-2.
Authors: Thomas W Linsky / Renan Vergara / Nuria Codina / Jorgen W Nelson / Matthew J Walker / Wen Su / Christopher O Barnes / Tien-Ying Hsiang / Katharina Esser-Nobis / Kevin Yu / Z Beau Reneer / ...Authors: Thomas W Linsky / Renan Vergara / Nuria Codina / Jorgen W Nelson / Matthew J Walker / Wen Su / Christopher O Barnes / Tien-Ying Hsiang / Katharina Esser-Nobis / Kevin Yu / Z Beau Reneer / Yixuan J Hou / Tanu Priya / Masaya Mitsumoto / Avery Pong / Uland Y Lau / Marsha L Mason / Jerry Chen / Alex Chen / Tania Berrocal / Hong Peng / Nicole S Clairmont / Javier Castellanos / Yu-Ru Lin / Anna Josephson-Day / Ralph S Baric / Deborah H Fuller / Carl D Walkey / Ted M Ross / Ryan Swanson / Pamela J Bjorkman / Michael Gale / Luis M Blancas-Mejia / Hui-Ling Yen / Daniel-Adriano Silva /
Abstract: We developed a de novo protein design strategy to swiftly engineer decoys for neutralizing pathogens that exploit extracellular host proteins to infect the cell. Our pipeline allowed the design, ...We developed a de novo protein design strategy to swiftly engineer decoys for neutralizing pathogens that exploit extracellular host proteins to infect the cell. Our pipeline allowed the design, validation, and optimization of de novo hACE2 decoys to neutralize SARS-CoV-2. The best decoy, CTC-445.2, binds with low nanomolar affinity and high specificity to the RBD of the spike protein. Cryo-EM shows that the design is accurate and can simultaneously bind to all three RBDs of a single spike protein. Because the decoy replicates the spike protein target interface in hACE2, it is intrinsically resilient to viral mutational escape. A bivalent decoy, CTC-445.2d, shows ~10-fold improvement in binding. CTC-445.2d potently neutralizes SARS-CoV-2 infection of cells in vitro and a single intranasal prophylactic dose of decoy protected Syrian hamsters from a subsequent lethal SARS-CoV-2 challenge.
History
DepositionOct 29, 2020-
Header (metadata) releaseNov 11, 2020-
Map releaseNov 11, 2020-
UpdateNov 25, 2020-
Current statusNov 25, 2020Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.12
  • Imaged by UCSF Chimera
  • Download
  • Surface view colored by cylindrical radius
  • Surface level: 0.12
  • Imaged by UCSF Chimera
  • Download
Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

Downloads & links

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Map

FileDownload / File: emd_22914.map.gz / Format: CCP4 / Size: 307.5 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.87 Å/pix.
x 432 pix.
= 375.408 Å
0.87 Å/pix.
x 432 pix.
= 375.408 Å
0.87 Å/pix.
x 432 pix.
= 375.408 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.869 Å
Density
Contour LevelBy AUTHOR: 0.105 / Movie #1: 0.12
Minimum - Maximum-0.3537072 - 0.7524439
Average (Standard dev.)-0.00012195952 (±0.021820871)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions432432432
Spacing432432432
CellA=B=C: 375.40802 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.8690.8690.869
M x/y/z432432432
origin x/y/z0.0000.0000.000
length x/y/z375.408375.408375.408
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ320320320
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS432432432
D min/max/mean-0.3540.752-0.000

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Supplemental data

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Sample components

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Entire Ternary complex of CTC445.2 inhibitor with SARS-CoV-2 S 6P glycoprotin

EntireName: Ternary complex of CTC445.2 inhibitor with SARS-CoV-2 S 6P glycoprotin
Number of components: 5

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Component #1: protein, Ternary complex of CTC445.2 inhibitor with SARS-CoV-2 S ...

ProteinName: Ternary complex of CTC445.2 inhibitor with SARS-CoV-2 S 6P glycoprotin
Recombinant expression: No
MassExperimental: 600 kDa

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Component #2: protein, Spike glycoprotein

ProteinName: Spike glycoproteinPeplomer / Recombinant expression: No
SourceSpecies: Severe acute respiratory syndrome coronavirus 2
Source (engineered)Expression System: Homo sapiens (human)

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Component #3: protein, CTC-445.2 inhibitor

ProteinName: CTC-445.2 inhibitor / Recombinant expression: No
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)

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Component #4: protein, SARS-CoV-2 stabilized 6P spike glycoprotein

ProteinName: SARS-CoV-2 stabilized 6P spike glycoprotein / Recombinant expression: No
SourceSpecies: Severe acute respiratory syndrome coronavirus 2
Source (engineered)Expression System: Homo sapiens (human)

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Component #5: protein, CTC-445.2 inhibitor

ProteinName: CTC-445.2 inhibitor / Recombinant expression: No
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)

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Experimental details

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Sample preparation

SpecimenSpecimen state: Particle / Method: cryo EM
Sample solutionSpecimen conc.: 3 mg/mL / pH: 8
Support film0.2 mA
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Temperature: 295 K / Humidity: 100 % / Details: 3s blot, 0 blot force.

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Electron microscopy imaging

Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company
ImagingMicroscope: FEI TALOS ARCTICA / Details: 3x3 beam tilt collection
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Electron dose: 60 e/Å2 / Illumination mode: FLOOD BEAM
LensMagnification: 45000 X (nominal) / Cs: 2.7 mm / Imaging mode: BRIGHT FIELD / Defocus: 800.0 - 2000.0 nm
Specimen HolderModel: FEI TITAN KRIOS AUTOGRID HOLDER
CameraDetector: OTHER

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Image acquisition

Image acquisitionNumber of digital images: 2250

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Image processing

ProcessingMethod: single particle reconstruction / Applied symmetry: C1 (asymmetric) / Number of projections: 47013
3D reconstructionSoftware: cryoSPARC / Resolution: 3.9 Å / Resolution method: FSC 0.143 CUT-OFF
FSC plot (resolution estimation)

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