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- EMDB-25690: SARS-CoV-2 S (Spike Glycoprotein) D614G with Three (3) RBDs Up, B... -

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Basic information

Entry
Database: EMDB / ID: EMD-25690
TitleSARS-CoV-2 S (Spike Glycoprotein) D614G with Three (3) RBDs Up, Bound to Antibody 2-7 scFv, local refinement map
Map data
Sample
  • Complex: Complex of SARS CoV-2 S, Spike Glycoprotein, variant D614G with Antibody 2-7 scFv
Biological speciesSevere acute respiratory syndrome coronavirus 2
Methodsingle particle reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsByrne PO / McLellan JS
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R01-AI127521 United States
CitationJournal: Nat Commun / Year: 2022
Title: IgG-like bispecific antibodies with potent and synergistic neutralization against circulating SARS-CoV-2 variants of concern.
Authors: Matthew R Chang / Luke Tomasovic / Natalia A Kuzmina / Adam J Ronk / Patrick O Byrne / Rebecca Johnson / Nadia Storm / Eduardo Olmedillas / Yixuan J Hou / Alexandra Schäfer / Sarah R Leist ...Authors: Matthew R Chang / Luke Tomasovic / Natalia A Kuzmina / Adam J Ronk / Patrick O Byrne / Rebecca Johnson / Nadia Storm / Eduardo Olmedillas / Yixuan J Hou / Alexandra Schäfer / Sarah R Leist / Longping V Tse / Hanzhong Ke / Christian Coherd / Katrina Nguyen / Maliwan Kamkaew / Anna Honko / Quan Zhu / Galit Alter / Erica Ollmann Saphire / Jason S McLellan / Anthony Griffiths / Ralph S Baric / Alexander Bukreyev / Wayne A Marasco /
Abstract: Monoclonal antibodies are a promising approach to treat COVID-19, however the emergence of SARS-CoV-2 variants has challenged the efficacy and future of these therapies. Antibody cocktails are being ...Monoclonal antibodies are a promising approach to treat COVID-19, however the emergence of SARS-CoV-2 variants has challenged the efficacy and future of these therapies. Antibody cocktails are being employed to mitigate these challenges, but neutralization escape remains a major challenge and alternative strategies are needed. Here we present two anti-SARS-CoV-2 spike binding antibodies, one Class 1 and one Class 4, selected from our non-immune human single-chain variable fragment (scFv) phage library, that are engineered into four, fully-human IgG-like bispecific antibodies (BsAb). Prophylaxis of hACE2 mice and post-infection treatment of golden hamsters demonstrates the efficacy of the monospecific antibodies against the original Wuhan strain, while promising in vitro results with the BsAbs demonstrate enhanced binding and distinct synergistic effects on neutralizing activity against circulating variants of concern. In particular, one BsAb engineered in a tandem scFv-Fc configuration shows synergistic neutralization activity against several variants of concern including B.1.617.2. This work provides evidence that synergistic neutralization can be achieved using a BsAb scaffold, and serves as a foundation for the future development of broadly reactive BsAbs against emerging variants of concern.
History
DepositionDec 10, 2021-
Header (metadata) releaseAug 24, 2022-
Map releaseAug 24, 2022-
UpdateMar 8, 2023-
Current statusMar 8, 2023Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_25690.png

Downloads & links

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Map

FileDownload / File: emd_25690.map.gz / Format: CCP4 / Size: 325 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
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Image control

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AxesZ (Sec.)Y (Row.)X (Col.)
0.9 Å/pix.
x 440 pix.
= 396. Å		0.9 Å/pix.
x 440 pix.
= 396. Å		0.9 Å/pix.
x 440 pix.
= 396. Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.9 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 2.0
Minimum - Maximum-1.1353354 - 5.48685
Average (Standard dev.)-0.014449837 (±0.10838555)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions440440440
Spacing440440440
CellA=B=C: 396.00003 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_25690_msk_1.map
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Additional map: #1

Fileemd_25690_additional_1.map
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Half map: #2

Fileemd_25690_half_map_1.map
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Half map: #1

Fileemd_25690_half_map_2.map
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Sample components

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Entire : Complex of SARS CoV-2 S, Spike Glycoprotein, variant D614G with A...

EntireName: Complex of SARS CoV-2 S, Spike Glycoprotein, variant D614G with Antibody 2-7 scFv
Components
  • Complex: Complex of SARS CoV-2 S, Spike Glycoprotein, variant D614G with Antibody 2-7 scFv

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Supramolecule #1: Complex of SARS CoV-2 S, Spike Glycoprotein, variant D614G with A...

SupramoleculeName: Complex of SARS CoV-2 S, Spike Glycoprotein, variant D614G with Antibody 2-7 scFv
type: complex / ID: 1 / Chimera: Yes / Parent: 0
Source (natural)Organism: Severe acute respiratory syndrome coronavirus 2

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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

Concentration0.5 mg/mL
BufferpH: 8
Component:
ConcentrationNameFormula
2.0 mMTris base
200.0 mMsodium chlorideNaCl
GridModel: UltrAuFoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Support film - Material: GOLD / Support film - topology: HOLEY / Pretreatment - Type: PLASMA CLEANING / Pretreatment - Time: 180 sec. / Pretreatment - Atmosphere: OTHER
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 293 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 70.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.5 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

7k8y

Final reconstructionNumber classes used: 1 / Applied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC
Details: Particle comprises a spike trimer complexed with three scFv molecules. Global refinement was performed in C3 on 17708 spike particles. Each spike contains three RBDs, three NTDs and three ...Details: Particle comprises a spike trimer complexed with three scFv molecules. Global refinement was performed in C3 on 17708 spike particles. Each spike contains three RBDs, three NTDs and three scFvs, related by a threefold symmetry axis. Symmetry expansion. Local refinement was performed in C1 after symmetry expansion in C3.
Number images used: 53124
Initial angle assignmentType: OTHER
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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