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- EMDB-18807: SD1-2 fab in complex with SARS-COV-2 BA.12.1 Spike Glycoprotein. -

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Basic information

Entry
Database: EMDB / ID: EMD-18807
TitleSD1-2 fab in complex with SARS-COV-2 BA.12.1 Spike Glycoprotein.
Map dataSharpened cryo-EM map of SD1-2 fab in complex with BA.2.12.1 Spike glycoprotein.
Sample
  • Complex: SD1-2 fab in complex with SARS-COV-2 BA.2.12.1 Spike Glycoprotein
    • Complex: SD1-2 fab
      • Protein or peptide: SD1-2 fab heavy chain
      • Protein or peptide: SD1-2 fab light chain
    • Complex: BA.2.12.1 Spike Glycoprotein Ectodomain
      • Protein or peptide: Spike glycoprotein,Fibritin
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
KeywordsSARS-CoV-2 / Spike / Glycoprotein / Coronavirus / antibody / fab / SD1 domain / therapeutic / complex / neutralisingm convalescent sera / viral protein / immune system / SD1-2 / BA.2.12.1 / omicron variant / virus / BA.2.86
Function / homology
Function and homology information


virion component / 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 ...virion component / 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 / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / 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
Fibritin C-terminal / Fibritin C-terminal region / 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 ...Fibritin C-terminal / Fibritin C-terminal region / 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
Spike glycoprotein / Fibritin
Similarity search - Component
Biological speciesSevere acute respiratory syndrome coronavirus 2 / Homo sapiens (human) / Enterobacteria phage T4 (virus)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.2 Å
AuthorsDuyvesteyn HME / Ren J / Stuart DI
Funding support United Kingdom, China, 4 items
OrganizationGrant numberCountry
Wellcome Trust203141/A/16/Z United Kingdom
Wellcome Trust101122/Z/13/Z United Kingdom
Chinese Academy of Sciences2018-I2M-2-002 China
Medical Research Council (MRC, United Kingdom)MR/N00065X/1 United Kingdom
CitationJournal: Nat Commun / Year: 2024
Title: The SARS-CoV-2 neutralizing antibody response to SD1 and its evasion by BA.2.86.
Authors: Daming Zhou / Piyada Supasa / Chang Liu / Aiste Dijokaite-Guraliuc / Helen M E Duyvesteyn / Muneeswaran Selvaraj / Alexander J Mentzer / Raksha Das / Wanwisa Dejnirattisai / Nigel Temperton ...Authors: Daming Zhou / Piyada Supasa / Chang Liu / Aiste Dijokaite-Guraliuc / Helen M E Duyvesteyn / Muneeswaran Selvaraj / Alexander J Mentzer / Raksha Das / Wanwisa Dejnirattisai / Nigel Temperton / Paul Klenerman / Susanna J Dunachie / Elizabeth E Fry / Juthathip Mongkolsapaya / Jingshan Ren / David I Stuart / Gavin R Screaton /
Abstract: Under pressure from neutralising antibodies induced by vaccination or infection the SARS-CoV-2 spike gene has become a hotspot for evolutionary change, leading to the failure of all mAbs developed ...Under pressure from neutralising antibodies induced by vaccination or infection the SARS-CoV-2 spike gene has become a hotspot for evolutionary change, leading to the failure of all mAbs developed for clinical use. Most potent antibodies bind to the receptor binding domain which has become heavily mutated. Here we study responses to a conserved epitope in sub-domain-1 (SD1) of spike which have become more prominent because of mutational escape from antibodies directed to the receptor binding domain. Some SD1 reactive mAbs show potent and broad neutralization of SARS-CoV-2 variants. We structurally map the dominant SD1 epitope and provide a mechanism of action by blocking interaction with ACE2. Mutations in SD1 have not been sustained to date, but one, E554K, leads to escape from mAbs. This mutation has now emerged in several sublineages including BA.2.86, reflecting selection pressure on the virus exerted by the increasing prominence of the anti-SD1 response.
History
DepositionNov 1, 2023-
Header (metadata) releaseMar 13, 2024-
Map releaseMar 13, 2024-
UpdateApr 10, 2024-
Current statusApr 10, 2024Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_18807.png

Downloads & links

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Map

FileDownload / File: emd_18807.map.gz / Format: CCP4 / Size: 48.5 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationSharpened cryo-EM map of SD1-2 fab in complex with BA.2.12.1 Spike glycoprotein.
Voxel sizeX=Y=Z: 0.7303 Å
Density
Contour LevelBy AUTHOR: 0.148
Minimum - Maximum-1.1863964 - 1.8716582
Average (Standard dev.)0.0070415335 (±0.08110213)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions225224252
Spacing224225252
CellA: 163.5872 Å / B: 164.3175 Å / C: 184.0356 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Half map A cryo-EM map of SD1-2 fab...

Fileemd_18807_half_map_1.map
AnnotationHalf map A cryo-EM map of SD1-2 fab in complex with BA.2.12.1 Spike glycoprotein.
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map B cryo-EM map of SD1-2 fab...

Fileemd_18807_half_map_2.map
AnnotationHalf map B cryo-EM map of SD1-2 fab in complex with BA.2.12.1 Spike glycoprotein.
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : SD1-2 fab in complex with SARS-COV-2 BA.2.12.1 Spike Glycoprotein

EntireName: SD1-2 fab in complex with SARS-COV-2 BA.2.12.1 Spike Glycoprotein
Components
  • Complex: SD1-2 fab in complex with SARS-COV-2 BA.2.12.1 Spike Glycoprotein
    • Complex: SD1-2 fab
      • Protein or peptide: SD1-2 fab heavy chain
      • Protein or peptide: SD1-2 fab light chain
    • Complex: BA.2.12.1 Spike Glycoprotein Ectodomain
      • Protein or peptide: Spike glycoprotein,Fibritin
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: SD1-2 fab in complex with SARS-COV-2 BA.2.12.1 Spike Glycoprotein

SupramoleculeName: SD1-2 fab in complex with SARS-COV-2 BA.2.12.1 Spike Glycoprotein
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Source (natural)Organism: Severe acute respiratory syndrome coronavirus 2

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Supramolecule #2: SD1-2 fab

SupramoleculeName: SD1-2 fab / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #2-#3
Details: Sequence from antibody isolated from convalescent sera.
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #3: BA.2.12.1 Spike Glycoprotein Ectodomain

SupramoleculeName: BA.2.12.1 Spike Glycoprotein Ectodomain / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #1 / Details: Has fibritin oligomerization tag
Source (natural)Organism: Severe acute respiratory syndrome coronavirus 2

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Macromolecule #1: Spike glycoprotein,Fibritin

MacromoleculeName: Spike glycoprotein,Fibritin / type: protein_or_peptide / ID: 1 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Enterobacteria phage T4 (virus)
Molecular weightTheoretical: 142.72925 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MFVFLVLLPL VSSQCVNLIT RTQSYTNSFT RGVYYPDKVF RSSVLHSTQD LFLPFFSNVT WFHAIHVSGT NGTKRFDNPV LPFNDGVYF ASTEKSNIIR GWIFGTTLDS KTQSLLIVNN ATNVVIKVCE FQFCNDPFLD VYYHKNNKSW MESEFRVYSS A NNCTFEYV ...String:
MFVFLVLLPL VSSQCVNLIT RTQSYTNSFT RGVYYPDKVF RSSVLHSTQD LFLPFFSNVT WFHAIHVSGT NGTKRFDNPV LPFNDGVYF ASTEKSNIIR GWIFGTTLDS KTQSLLIVNN ATNVVIKVCE FQFCNDPFLD VYYHKNNKSW MESEFRVYSS A NNCTFEYV SQPFLMDLEG KQGNFKNLRE FVFKNIDGYF KIYSKHTPIN LGRDLPQGFS ALEPLVDLPI GINITRFQTL LA LHRSYLT PGDSSSGWTA GAAAYYVGYL QPRTFLLKYN ENGTITDAVD CALDPLSETK CTLKSFTVEK GIYQTSNFRV QPT ESIVRF PNITNLCPFD EVFNATRFAS VYAWNRKRIS NCVADYSVLY NFAPFFAFKC YGVSPTKLND LCFTNVYADS FVIR GNEVS QIAPGQTGNI ADYNYKLPDD FTGCVIAWNS NKLDSKVGGN YNYQYRLFRK SNLKPFERDI STEIYQAGNK PCNGV AGFN CYFPLRSYGF RPTYGVGHQP YRVVVLSFEL LHAPATVCGP KKSTNLVKNK CVNFNFNGLT GTGVLTESNK KFLPFQ QFG RDIADTTDAV RDPQTLEILD ITPCSFGGVS VITPGTNTSN QVAVLYQGVN CTEVPVAIHA DQLTPTWRVY STGSNVF QT RAGCLIGAEY VNNSYECDIP IGAGICASYQ TQTKSHRRAR SVASQSIIAY TMSLGAENLV AYSNNSIAIP TNFTISVT T EILPVSMTKT SVDCTMYICG DSTECSNLLL QYGSFCTQLK RALTGIAVEQ DKNTQEVFAQ VKQIYKTPPI KYFGGFNFS QILPDPSKPS KRSFIEDLLF NKVTLADAGF IKQYGDCLGD IAARDLICAQ KFNGLTVLPP LLTDEMIAQY TSALLAGTIT SGWTFGAGA ALQIPFAMQM AYRFNGIGVT QNVLYENQKL IANQFNSAIG KIQDSLSSTA SALGKLQDVV NHNAQALNTL V KQLSSKFG AISSVLNDIL SRLDKVEAEV QIDRLITGRL QSLQTYVTQQ LIRAAEIRAS ANLAATKMSE CVLGQSKRVD FC GKGYHLM SFPQSAPHGV VFLHVTYVPA QEKNFTTAPA ICHDGKAHFP REGVFVSNGT HWFVTQRNFY EPQIITTDNT FVS GNCDVV IGIVNNTVYD PLQPELDSFK EELDKYFKNH TSPDVDLGDI SGINASVVNI QKEIDRLNEV AKNLNESLID LQEL GKYEQ GSGYIPEAPR DGQAYVRKDG EWVLLSTFLG RSLEVLFQGP GHHHHHHHHG SAWSHPQFEK GGGSGGGSGG SAWSH PQFE K

UniProtKB: Spike glycoprotein, Fibritin

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Macromolecule #2: SD1-2 fab heavy chain

MacromoleculeName: SD1-2 fab heavy chain / type: protein_or_peptide / ID: 2 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 13.274797 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
QVQLVQSGPG LVKPSQTLSL TCSVSGDSIS SGTYYWSWIR LPAGQGLEWI GRVHSSGSTS YNPSLKSRVT ISVDTSKNNF SLKLSSVTA ADTAVYYCVR LDNCSAGYCH AFDIWGQGTM VTVSS

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Macromolecule #3: SD1-2 fab light chain

MacromoleculeName: SD1-2 fab light chain / type: protein_or_peptide / ID: 3 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 11.468586 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
QSVLTQPASV SGSPGQSITI SCTGTSSDVG SYNLVSWYQQ HPGKAPKVMI YEVSKWPSGV SNRFSGSKSG NTASLTISGL QAEDEADYY CCSYAGSGTY VFGTGTKVTV L

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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: 30 / 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

Concentration0.7 mg/mL
BufferpH: 7.4
GridModel: C-flat-2/1 / Material: COPPER / Mesh: 200 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 20 sec. / Pretreatment - Atmosphere: AIR / Details: Harrick Plasma unit.
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277.5 K / Instrument: FEI VITROBOT MARK IV
DetailsSpike ectodomain incubated with SD1-2 fab in 2-fold molecular excess of sites (assuming three per trimeric spike unit).

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 50.0 µm / Calibrated magnification: 165000 / Illumination mode: OTHER / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm / Nominal defocus max: 2.6 µm / Nominal defocus min: 0.8 µm
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 50.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 764482 / Details: Blob picker in cryoSPARC live interface.
Startup modelType of model: INSILICO MODEL
In silico model: Ab initio model generated in cryoSPARC from 21,480 randomly selected picked particles.
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final 3D classificationNumber classes: 250 / Software - Name: cryoSPARC
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final reconstructionApplied symmetry - Point group: C3 (3 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 2.2 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Details: Estimation determined by cryoSPARC. / Number images used: 503734

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Atomic model buiding 1

Initial modelPDB ID:

8cim


Chain - Source name: PDB / Chain - Initial model type: experimental model
RefinementSpace: REAL / Protocol: RIGID BODY FIT / Overall B value: 68
Output model

PDB-8r1c:
SD1-2 Fab in complex with SARS-CoV-2 BA.2.12.1 Spike Glycoprotein

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