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- EMDB-28199: Cryo-EM map of SARS-CoV-2 Omicron BA.2 spike in complex with 2130... -

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Basic information

Entry
Database: EMDB / ID: EMD-28199
TitleCryo-EM map of SARS-CoV-2 Omicron BA.2 spike in complex with 2130-1-0114-112
Map data
Sample
  • Complex: SARS Cov2 Omicron BA.2 RBD complex with Fab LLNL-199
    • Complex: SARS Cov2 Omicron BA.2 RBD
      • Protein or peptide: Spike protein S2'
    • Complex: Fab LLNL-199
      • Protein or peptide: Fab LLNL-199 HC
      • Protein or peptide: Fab LLNL-199 LC
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
KeywordsFab / Cov2 / BA.2 / Omicron / IMMUNE SYSTEM
Function / homology
Function and homology information


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 ...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 / 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
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 ...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
Biological speciesSevere acute respiratory syndrome coronavirus / Homo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.6 Å
AuthorsBinshtein E / Crowe JE
Funding support United States, 2 items
OrganizationGrant numberCountry
Defense Advanced Research Projects Agency (DARPA)HR0011-18-3-0001 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)AI157155 United States
CitationJournal: Nature / Year: 2024
Title: Computationally restoring the potency of a clinical antibody against Omicron.
Authors: Thomas A Desautels / Kathryn T Arrildt / Adam T Zemla / Edmond Y Lau / Fangqiang Zhu / Dante Ricci / Stephanie Cronin / Seth J Zost / Elad Binshtein / Suzanne M Scheaffer / Bernadeta ...Authors: Thomas A Desautels / Kathryn T Arrildt / Adam T Zemla / Edmond Y Lau / Fangqiang Zhu / Dante Ricci / Stephanie Cronin / Seth J Zost / Elad Binshtein / Suzanne M Scheaffer / Bernadeta Dadonaite / Brenden K Petersen / Taylor B Engdahl / Elaine Chen / Laura S Handal / Lynn Hall / John W Goforth / Denis Vashchenko / Sam Nguyen / Dina R Weilhammer / Jacky Kai-Yin Lo / Bonnee Rubinfeld / Edwin A Saada / Tracy Weisenberger / Tek-Hyung Lee / Bradley Whitener / James B Case / Alexander Ladd / Mary S Silva / Rebecca M Haluska / Emilia A Grzesiak / Christopher G Earnhart / Svetlana Hopkins / Thomas W Bates / Larissa B Thackray / Brent W Segelke / / Antonietta Maria Lillo / Shivshankar Sundaram / Jesse D Bloom / Michael S Diamond / James E Crowe / Robert H Carnahan / Daniel M Faissol /
Abstract: The COVID-19 pandemic underscored the promise of monoclonal antibody-based prophylactic and therapeutic drugs and revealed how quickly viral escape can curtail effective options. When the SARS-CoV-2 ...The COVID-19 pandemic underscored the promise of monoclonal antibody-based prophylactic and therapeutic drugs and revealed how quickly viral escape can curtail effective options. When the SARS-CoV-2 Omicron variant emerged in 2021, many antibody drug products lost potency, including Evusheld and its constituent, cilgavimab. Cilgavimab, like its progenitor COV2-2130, is a class 3 antibody that is compatible with other antibodies in combination and is challenging to replace with existing approaches. Rapidly modifying such high-value antibodies to restore efficacy against emerging variants is a compelling mitigation strategy. We sought to redesign and renew the efficacy of COV2-2130 against Omicron BA.1 and BA.1.1 strains while maintaining efficacy against the dominant Delta variant. Here we show that our computationally redesigned antibody, 2130-1-0114-112, achieves this objective, simultaneously increases neutralization potency against Delta and subsequent variants of concern, and provides protection in vivo against the strains tested: WA1/2020, BA.1.1 and BA.5. Deep mutational scanning of tens of thousands of pseudovirus variants reveals that 2130-1-0114-112 improves broad potency without increasing escape liabilities. Our results suggest that computational approaches can optimize an antibody to target multiple escape variants, while simultaneously enriching potency. Our computational approach does not require experimental iterations or pre-existing binding data, thus enabling rapid response strategies to address escape variants or lessen escape vulnerabilities.
History
DepositionSep 20, 2022-
Header (metadata) releaseFeb 21, 2024-
Map releaseFeb 21, 2024-
UpdateJun 19, 2024-
Current statusJun 19, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_28199.png

Downloads & links

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Map

FileDownload / File: emd_28199.map.gz / Format: CCP4 / Size: 8 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.29 Å/pix.
x 128 pix.
= 165.632 Å		1.29 Å/pix.
x 128 pix.
= 165.632 Å		1.29 Å/pix.
x 128 pix.
= 165.632 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.294 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 1.0
Minimum - Maximum-9.245405999999999 - 13.406726000000001
Average (Standard dev.)0.0032337669 (±0.27786586)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions128128128
Spacing128128128
CellA=B=C: 165.632 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_28199_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_28199_half_map_2.map
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 Cov2 Omicron BA.2 RBD complex with Fab LLNL-199

EntireName: SARS Cov2 Omicron BA.2 RBD complex with Fab LLNL-199
Components
  • Complex: SARS Cov2 Omicron BA.2 RBD complex with Fab LLNL-199
    • Complex: SARS Cov2 Omicron BA.2 RBD
      • Protein or peptide: Spike protein S2'
    • Complex: Fab LLNL-199
      • Protein or peptide: Fab LLNL-199 HC
      • Protein or peptide: Fab LLNL-199 LC
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: SARS Cov2 Omicron BA.2 RBD complex with Fab LLNL-199

SupramoleculeName: SARS Cov2 Omicron BA.2 RBD complex with Fab LLNL-199 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2

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Supramolecule #2: SARS Cov2 Omicron BA.2 RBD

SupramoleculeName: SARS Cov2 Omicron BA.2 RBD / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #3
Source (natural)Organism: Severe acute respiratory syndrome coronavirus

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Supramolecule #3: Fab LLNL-199

SupramoleculeName: Fab LLNL-199 / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Fab LLNL-199 HC

MacromoleculeName: Fab LLNL-199 HC / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 14.310997 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
EVQLVESGGG LVKPGGSLRL SCAASGFTFR DVWMSWVRQA PGKGLEWVGR IKSKIDGGTT DYAAPVKGRF TISRDDSKNT LYLQMNSLK TEDTAVYYCT TAGSYYYDTV GPELPEGKFD YWGQGTLVTV SS

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Macromolecule #2: Fab LLNL-199 LC

MacromoleculeName: Fab LLNL-199 LC / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 12.470904 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
DIVMTQSPDS LAVSLGERAT INCKSSQSVL YAANNKNYLA WYQQKPGQPP KLLMYWASER ESGVPDRFSG SGSGAEFTLT ISSLQAEDV AIYYCQQYYS TLTFGGGTKV EIKR

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Macromolecule #3: Spike protein S2'

MacromoleculeName: Spike protein S2' / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Severe acute respiratory syndrome coronavirus
Molecular weightTheoretical: 20.978592 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
TNLCPFDEVF NATRFASVYA WNRKRISNCV ADYSVLYNFA PFFAFKCYGV SPTKLNDLCF TNVYADSFVI RGNEVSQIAP GQTGNIADY NYKLPDDFTG CVIAWNSNKL DSKVGGNYNY LYRLFRKSNL KPFERDISTE IYQAGNKPCN GVAGFNCYFP L RSYGFRPT YGVGHQPYRV VVLSFE

UniProtKB: Spike glycoprotein

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Macromolecule #4: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 4 / Number of copies: 1 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

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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

Concentration0.6 mg/mL
BufferpH: 8
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 293.15 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm / Nominal defocus max: 1.8 µm / Nominal defocus min: 0.8 µm / Nominal magnification: 130000
Specialist opticsEnergy filter - Name: GIF Bioquantum / Energy filter - Slit width: 20 eV
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Number grids imaged: 1 / Number real images: 23469 / Average exposure time: 1.5 sec. / Average electron dose: 52.173 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: INSILICO MODEL
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 4)
Final 3D classificationSoftware - Name: RELION (ver. 4)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 4)
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 4) / Number images used: 386950
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial model
PDB IDChain

7l7e

chain_id: E, source_name: PDB, initial_model_type: experimental model

7l7e

chain_id: F, source_name: PDB, initial_model_type: experimental model

7l7e

chain_id: G, source_name: PDB, initial_model_type: experimental model
RefinementSpace: REAL
Output model

PDB-8ekd:
Cryo-EM map of SARS-CoV-2 Omicron BA.2 spike in complex with 2130-1-0114-112

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