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- EMDB-28198: Cryo-EM map of SARS-CoV-2 Omicron BA.2 spike in complex with LLNL-199 -

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Basic information

Entry
Database: EMDB / ID: EMD-28198
TitleCryo-EM map of SARS-CoV-2 Omicron BA.2 spike in complex with LLNL-199
Map data
Sample
  • Complex: SARS Cov2 Omicron BA.2 complex with Fab LLNL-199
    • Complex: SARS Cov2 Omicron BA.2 spike
    • Complex: Fab LLNL-199
KeywordsFab / Cov2 / BA.2 / Omicron / IMMUNE SYSTEM
Biological speciesHomo sapiens (human) / Severe acute respiratory syndrome coronavirus
Methodsingle particle reconstruction / cryo EM / Resolution: 3.26 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_28198.png

Downloads & links

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Map

FileDownload / File: emd_28198.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.294 Å
Density
Contour LevelBy AUTHOR: 0.01
Minimum - Maximum-0.0693966 - 0.119205505
Average (Standard dev.)0.000041117804 (±0.002181242)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 388.2 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_28198_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_28198_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 complex with Fab LLNL-199

EntireName: SARS Cov2 Omicron BA.2 complex with Fab LLNL-199
Components
  • Complex: SARS Cov2 Omicron BA.2 complex with Fab LLNL-199
    • Complex: SARS Cov2 Omicron BA.2 spike
    • Complex: Fab LLNL-199

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

SupramoleculeName: SARS Cov2 Omicron BA.2 complex with Fab LLNL-199 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#7
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #2: SARS Cov2 Omicron BA.2 spike

SupramoleculeName: SARS Cov2 Omicron BA.2 spike / type: complex / ID: 2 / Parent: 1
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
Source (natural)Organism: Homo sapiens (human)

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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
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
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 1.8 µm / Nominal defocus min: 0.8 µm / Nominal magnification: 130000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.26 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 4) / Number images used: 291461
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 4)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 4)
Final 3D classificationSoftware - Name: RELION (ver. 4)
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementSpace: REAL

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