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- EMDB-22735: Structure of the SARS-CoV-2 S 2P trimer in complex with the human... -

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Basic information

Entry
Database: EMDB / ID: EMD-22735
TitleStructure of the SARS-CoV-2 S 2P trimer in complex with the human neutralizing antibody Fab fragment, C121 (State 2)
Map data
SampleTernary complex of SARS-CoV-2 S 2P trimer with human neutralizing antibody Fab fragment C121 (state 2):
SARS-CoV-2 S 2P glycoprotein / neutralizing antibody Fab fragment C121 / Spike glycoproteinPeplomer / C121 Fab Heavy chain / C121 Fab Light chain / ligand
Function / homology
Function and homology information


suppression by virus of host tetherin activity / host cell endoplasmic reticulum-Golgi intermediate compartment membrane / receptor-mediated virion attachment to host cell / endoplasmic reticulum-Golgi intermediate compartment / viral translation / host cell surface receptor binding / endocytosis involved in viral entry into host cell / endocytic vesicle membrane / fusion of virus membrane with host plasma membrane / viral protein processing ...suppression by virus of host tetherin activity / host cell endoplasmic reticulum-Golgi intermediate compartment membrane / receptor-mediated virion attachment to host cell / endoplasmic reticulum-Golgi intermediate compartment / viral translation / host cell surface receptor binding / endocytosis involved in viral entry into host cell / endocytic vesicle membrane / fusion of virus membrane with host plasma membrane / viral protein processing / suppression by virus of host type I interferon-mediated signaling pathway / fusion of virus membrane with host endosome membrane / viral envelope / viral entry into host cell / go:0009405: / endoplasmic reticulum lumen / host cell plasma membrane / virion membrane / integral component of membrane / identical protein binding
Spike receptor binding domain superfamily, coronavirus / Spike (S) protein S1 subunit, N-terminal domain, SARS-CoV-like / Spike glycoprotein S2 superfamily, coronavirus / Coronavirus spike glycoprotein S1, C-terminal / Spike glycoprotein, betacoronavirus / Spike (S) protein S1 subunit, receptor-binding domain, betacoronavirus / Spike glycoprotein S2, coronavirus / Spike (S) protein S1 subunit, receptor-binding domain, SARS-CoV-2 / in:ipr027400: / Spike glycoprotein S1, N-terminal domain, betacoronavirus-like
Spike glycoprotein
Biological speciesSevere acute respiratory syndrome coronavirus 2 / Homo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.4 Å
AuthorsAbernathy ME / Barnes CO / Bjorkman PJ
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)P01-AI138938-S1 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)P50-AI150464-13 United States
CitationJournal: Nature / Year: 2020
Title: SARS-CoV-2 neutralizing antibody structures inform therapeutic strategies.
Authors: Christopher O Barnes / Claudia A Jette / Morgan E Abernathy / Kim-Marie A Dam / Shannon R Esswein / Harry B Gristick / Andrey G Malyutin / Naima G Sharaf / Kathryn E Huey-Tubman / Yu E Lee / ...Authors: Christopher O Barnes / Claudia A Jette / Morgan E Abernathy / Kim-Marie A Dam / Shannon R Esswein / Harry B Gristick / Andrey G Malyutin / Naima G Sharaf / Kathryn E Huey-Tubman / Yu E Lee / Davide F Robbiani / Michel C Nussenzweig / Anthony P West / Pamela J Bjorkman /
Abstract: The coronavirus disease 2019 (COVID-19) pandemic presents an urgent health crisis. Human neutralizing antibodies that target the host ACE2 receptor-binding domain (RBD) of the severe acute ...The coronavirus disease 2019 (COVID-19) pandemic presents an urgent health crisis. Human neutralizing antibodies that target the host ACE2 receptor-binding domain (RBD) of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) spike protein show promise therapeutically and are being evaluated clinically. Here, to identify the structural correlates of SARS-CoV-2 neutralization, we solved eight new structures of distinct COVID-19 human neutralizing antibodies in complex with the SARS-CoV-2 spike trimer or RBD. Structural comparisons allowed us to classify the antibodies into categories: (1) neutralizing antibodies encoded by the VH3-53 gene segment with short CDRH3 loops that block ACE2 and bind only to 'up' RBDs; (2) ACE2-blocking neutralizing antibodies that bind both up and 'down' RBDs and can contact adjacent RBDs; (3) neutralizing antibodies that bind outside the ACE2 site and recognize both up and down RBDs; and (4) previously described antibodies that do not block ACE2 and bind only to up RBDs. Class 2 contained four neutralizing antibodies with epitopes that bridged RBDs, including a VH3-53 antibody that used a long CDRH3 with a hydrophobic tip to bridge between adjacent down RBDs, thereby locking the spike into a closed conformation. Epitope and paratope mapping revealed few interactions with host-derived N-glycans and minor contributions of antibody somatic hypermutations to epitope contacts. Affinity measurements and mapping of naturally occurring and in vitro-selected spike mutants in 3D provided insight into the potential for SARS-CoV-2 to escape from antibodies elicited during infection or delivered therapeutically. These classifications and structural analyses provide rules for assigning current and future human RBD-targeting antibodies into classes, evaluating avidity effects and suggesting combinations for clinical use, and provide insight into immune responses against SARS-CoV-2.
Validation ReportSummary, Full report, XML, About validation report
History
DepositionSep 27, 2020-
Header (metadata) releaseOct 21, 2020-
Map releaseOct 21, 2020-
UpdateJan 13, 2021-
Current statusJan 13, 2021Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.06
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.06
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7k8y
  • Surface level: 0.06
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

Downloads & links

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Map

FileDownload / File: emd_22735.map.gz / Format: CCP4 / Size: 352.3 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.84 Å/pix.
x 452 pix.
= 377.872 Å
0.84 Å/pix.
x 452 pix.
= 377.872 Å
0.84 Å/pix.
x 452 pix.
= 377.872 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.836 Å
Density
Contour LevelBy AUTHOR: 0.0555 / Movie #1: 0.06
Minimum - Maximum-0.08990264 - 0.28155127
Average (Standard dev.)0.00043788945 (±0.011951806)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions452452452
Spacing452452452
CellA=B=C: 377.872 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.8360.8360.836
M x/y/z452452452
origin x/y/z0.0000.0000.000
length x/y/z377.872377.872377.872
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ304304304
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS452452452
D min/max/mean-0.0900.2820.000

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Supplemental data

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Additional map: un-sharpened main map

Fileemd_22735_additional_1.map
Annotationun-sharpened main map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

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Sample components

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Entire Ternary complex of SARS-CoV-2 S 2P trimer with human neutralizing...

EntireName: Ternary complex of SARS-CoV-2 S 2P trimer with human neutralizing antibody Fab fragment C121 (state 2)
Number of components: 7

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Component #1: protein, Ternary complex of SARS-CoV-2 S 2P trimer with human neu...

ProteinName: Ternary complex of SARS-CoV-2 S 2P trimer with human neutralizing antibody Fab fragment C121 (state 2)
Recombinant expression: No
MassExperimental: 720 kDa

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Component #2: protein, SARS-CoV-2 S 2P glycoprotein

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

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Component #3: protein, neutralizing antibody Fab fragment C121

ProteinName: neutralizing antibody Fab fragment C121 / Recombinant expression: No
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Homo sapiens (human)

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Component #4: protein, Spike glycoprotein

ProteinName: Spike glycoproteinPeplomer / Number of Copies: 3 / Recombinant expression: No
MassTheoretical: 139.787969 kDa
SourceSpecies: Severe acute respiratory syndrome coronavirus 2
Source (engineered)Expression System: Homo sapiens (human)

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Component #5: protein, C121 Fab Heavy chain

ProteinName: C121 Fab Heavy chain / Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 25.965162 kDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Homo sapiens (human)

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Component #6: protein, C121 Fab Light chain

ProteinName: C121 Fab Light chain / Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 22.619984 kDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Homo sapiens (human)

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Component #7: ligand, 2-acetamido-2-deoxy-beta-D-glucopyranose

LigandName: 2-acetamido-2-deoxy-beta-D-glucopyranose / Number of Copies: 23 / Recombinant expression: No
MassTheoretical: 0.221208 kDa

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Experimental details

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Sample preparation

SpecimenSpecimen state: Particle / Method: cryo EM
Sample solutionSpecimen conc.: 2.5 mg/mL / pH: 8
Support film0.2 mA
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Temperature: 295 K / Humidity: 100 % / Details: 3s blot.

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
ImagingMicroscope: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Electron dose: 60 e/Å2 / Illumination mode: FLOOD BEAM
LensMagnification: 105000 X (nominal) / Cs: 2.7 mm / Imaging mode: BRIGHT FIELD / Defocus: 1000.0 - 2500.0 nm / Energy filter: GIF Bioquantum
Specimen HolderModel: FEI TITAN KRIOS AUTOGRID HOLDER
CameraDetector: OTHER

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Image acquisition

Image acquisitionNumber of digital images: 5481

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Image processing

ProcessingMethod: single particle reconstruction / Applied symmetry: C1 (asymmetric) / Number of projections: 14999
3D reconstructionSoftware: cryoSPARC / Resolution: 4.4 Å / Resolution method: FSC 0.143 CUT-OFF
FSC plot (resolution estimation)

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Atomic model buiding

Modeling #1Refinement protocol: rigid body / Refinement space: REAL
Input PDB model: 6VXX, 6W41
Output model

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