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- EMDB-36850: SARS-CoV-2 Omicron BA.1 spike protein in complex with a self-asse... -

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Basic information

Entry
Database: EMDB / ID: EMD-36850
TitleSARS-CoV-2 Omicron BA.1 spike protein in complex with a self-assembling trivalent nanobody Tr67
Map dataSARS-CoV-2 Omicron BA.1 spike protein in complex with a self-assembling trivalent nanobody Tr67
Sample
  • Complex: SARS-CoV-2 Omicron BA.1 spike protein in complex with a self-assembling trivalent nanobody Tr67
    • Complex: Trivalent nanobody
    • Complex: SARS-CoV-2 Omicron BA.1 spike protein
Keywordstrivalent nanobody / viral neutralization / Omicron BA.1 / 3-RBD-up conformation / VIRAL PROTEIN
Biological speciesSevere acute respiratory syndrome coronavirus 2 / synthetic construct (others)
Methodsingle particle reconstruction / cryo EM / Resolution: 9.0 Å
AuthorsJiang XY / Qin Q / Qian JQ / Zhu HX / Huang Q
Funding support China, 2 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)31971377 China
National Natural Science Foundation of China (NSFC)31671386 China
CitationJournal: J Nanobiotechnology / Year: 2024
Title: Computational design and engineering of self-assembling multivalent microproteins with therapeutic potential against SARS-CoV-2.
Authors: Qin Qin / Xinyi Jiang / Liyun Huo / Jiaqiang Qian / Hongyuan Yu / Haixia Zhu / Wenhao Du / Yuhui Cao / Xing Zhang / Qiang Huang /
Abstract: Multivalent drugs targeting homo-oligomeric viral surface proteins, such as the SARS-CoV-2 trimeric spike (S) protein, have the potential to elicit more potent and broad-spectrum therapeutic ...Multivalent drugs targeting homo-oligomeric viral surface proteins, such as the SARS-CoV-2 trimeric spike (S) protein, have the potential to elicit more potent and broad-spectrum therapeutic responses than monovalent drugs by synergistically engaging multiple binding sites on viral targets. However, rational design and engineering of nanoscale multivalent protein drugs are still lacking. Here, we developed a computational approach to engineer self-assembling trivalent microproteins that simultaneously bind to the three receptor binding domains (RBDs) of the S protein. This approach involves four steps: structure-guided linker design, molecular simulation evaluation of self-assembly, experimental validation of self-assembly state, and functional testing. Using this approach, we first designed trivalent constructs of the microprotein miniACE2 (MP) with different trimerization scaffolds and linkers, and found that one of the constructs (MP-5ff) showed high trimerization efficiency, good conformational homogeneity, and strong antiviral neutralizing activity. With its trimerization unit (5ff), we then engineered a trivalent nanobody (Tr67) that exhibited potent and broad neutralizing activity against the dominant Omicron variants, including XBB.1 and XBB.1.5. Cryo-EM complex structure confirmed that Tr67 stably binds to all three RBDs of the Omicron S protein in a synergistic form, locking them in the "3-RBD-up" conformation that could block human receptor (ACE2) binding and potentially facilitate immune clearance. Therefore, our approach provides an effective strategy for engineering potent protein drugs against SARS-CoV-2 and other deadly coronaviruses.
History
DepositionJul 15, 2023-
Header (metadata) releaseMay 8, 2024-
Map releaseMay 8, 2024-
UpdateMay 8, 2024-
Current statusMay 8, 2024Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_36850.png

Downloads & links

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Map

FileDownload / File: emd_36850.map.gz / Format: CCP4 / Size: 83.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationSARS-CoV-2 Omicron BA.1 spike protein in complex with a self-assembling trivalent nanobody Tr67
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.57 Å/pix.
x 280 pix.
= 439.6 Å		1.57 Å/pix.
x 280 pix.
= 439.6 Å		1.57 Å/pix.
x 280 pix.
= 439.6 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.57 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.015
Minimum - Maximum-0.021311618 - 0.0718388
Average (Standard dev.)0.000026341284 (±0.004484539)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions280280280
Spacing280280280
CellA=B=C: 439.6 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: SARS-CoV-2 Omicron BA.1 spike protein in complex with...

Fileemd_36850_additional_1.map
AnnotationSARS-CoV-2 Omicron BA.1 spike protein in complex with a self-assembling trivalent nanobody Tr67
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map 1

Fileemd_36850_half_map_1.map
AnnotationHalf map 1
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map 2

Fileemd_36850_half_map_2.map
AnnotationHalf map 2
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : SARS-CoV-2 Omicron BA.1 spike protein in complex with a self-asse...

EntireName: SARS-CoV-2 Omicron BA.1 spike protein in complex with a self-assembling trivalent nanobody Tr67
Components
  • Complex: SARS-CoV-2 Omicron BA.1 spike protein in complex with a self-assembling trivalent nanobody Tr67
    • Complex: Trivalent nanobody
    • Complex: SARS-CoV-2 Omicron BA.1 spike protein

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Supramolecule #1: SARS-CoV-2 Omicron BA.1 spike protein in complex with a self-asse...

SupramoleculeName: SARS-CoV-2 Omicron BA.1 spike protein in complex with a self-assembling trivalent nanobody Tr67
type: complex / ID: 1 / Parent: 0
Source (natural)Organism: Severe acute respiratory syndrome coronavirus 2

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Supramolecule #2: Trivalent nanobody

SupramoleculeName: Trivalent nanobody / type: complex / ID: 2 / Parent: 1
Source (natural)Organism: synthetic construct (others)

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Supramolecule #3: SARS-CoV-2 Omicron BA.1 spike protein

SupramoleculeName: SARS-CoV-2 Omicron BA.1 spike protein / type: complex / ID: 3 / Parent: 1
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 state3D array

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Sample preparation

Concentration0.3 mg/mL
BufferpH: 7.4
Component:
ConcentrationFormulaName
150.0 mMNaClSodium chloridesodium chloride
10.0 mMC8H18N2O4SHEPES
1.0 %C3H8O3glycerol

Details: 10 mM HEPES,150 mM NaCl,1% glycerol
GridModel: Quantifoil / Material: COPPER / Mesh: 200 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 60 sec. / Pretreatment - Atmosphere: AIR
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 296.15 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS GLACIOS
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: SPOT SCAN / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2.4 µm / Nominal defocus min: 1.8 µm / Nominal magnification: 92000
Image recordingFilm or detector model: FEI FALCON III (4k x 4k) / Average electron dose: 43.0 e/Å2

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Image processing

Startup modelType of model: OTHER
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 5.0)
Final 3D classificationNumber classes: 3 / Avg.num./class: 28788 / Software - Name: RELION (ver. 5.0)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 5.0)
Final reconstructionNumber classes used: 1 / Applied symmetry - Point group: C3 (3 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 9.0 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 5.0) / Number images used: 38780
FSC plot (resolution estimation)

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