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- EMDB-14628: SARS-CoV-2 Spike protein in complex with the single chain fragmen... -

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Basic information

Entry
Database: EMDB / ID: EMD-14628
TitleSARS-CoV-2 Spike protein in complex with the single chain fragment scFv76Coronavirus spike protein
Map datasharped
Sample
  • Complex: SARS-CoV-2 Spike protein in complex with the single chain fragment scFv76Coronavirus spike protein
    • Complex: SARS-CoV-2 Spike proteinCoronavirus spike protein
      • Protein or peptide: Spike glycoprotein,Fibritin
    • Complex: scFv76 single chain fragment
      • Protein or peptide: scFv76 single chain fragment
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
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: 3.5 Å
AuthorsChaves-Sanjuan A / Bolognesi M
Funding support1 items
OrganizationGrant numberCountry
Not funded
CitationJournal: Mol Ther / Year: 2023
Title: Spike mutation resilient scFv76 antibody counteracts SARS-CoV-2 lung damage upon aerosol delivery.
Authors: Ferdinando M Milazzo / Antonio Chaves-Sanjuan / Olga Minenkova / Daniela Santapaola / Anna M Anastasi / Gianfranco Battistuzzi / Caterina Chiapparino / Antonio Rosi / Emilio Merlo Pich / ...Authors: Ferdinando M Milazzo / Antonio Chaves-Sanjuan / Olga Minenkova / Daniela Santapaola / Anna M Anastasi / Gianfranco Battistuzzi / Caterina Chiapparino / Antonio Rosi / Emilio Merlo Pich / Claudio Albertoni / Emanuele Marra / Laura Luberto / Cécile Viollet / Luigi G Spagnoli / Anna Riccio / Antonio Rossi / M Gabriella Santoro / Federico Ballabio / Cristina Paissoni / Carlo Camilloni / Martino Bolognesi / Rita De Santis /
Abstract: The uneven worldwide vaccination coverage against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and emergence of variants escaping immunity call for broadly effective and easily ...The uneven worldwide vaccination coverage against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and emergence of variants escaping immunity call for broadly effective and easily deployable therapeutic agents. We have previously described the human single-chain scFv76 antibody, which recognizes SARS-CoV-2 Alpha, Beta, Gamma and Delta variants. We now show that scFv76 also neutralizes the infectivity and fusogenic activity of the Omicron BA.1 and BA.2 variants. Cryoelectron microscopy (cryo-EM) analysis reveals that scFv76 binds to a well-conserved SARS-CoV-2 spike epitope, providing the structural basis for its broad-spectrum activity. We demonstrate that nebulized scFv76 has therapeutic efficacy in a severe hACE2 transgenic mouse model of coronavirus disease 2019 (COVID-19) pneumonia, as shown by body weight and pulmonary viral load data. Counteraction of infection correlates with inhibition of lung inflammation, as observed by histopathology and expression of inflammatory cytokines and chemokines. Biomarkers of pulmonary endothelial damage were also significantly reduced in scFv76-treated mice. The results support use of nebulized scFv76 for COVID-19 induced by any SARS-CoV-2 variants that have emerged so far.
History
DepositionMar 28, 2022-
Header (metadata) releaseOct 12, 2022-
Map releaseOct 12, 2022-
UpdateFeb 8, 2023-
Current statusFeb 8, 2023Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_14628.png

Downloads & links

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Map

FileDownload / File: emd_14628.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationsharped
Voxel sizeX=Y=Z: 0.889 Å
Density
Contour LevelBy AUTHOR: 0.3
Minimum - Maximum-2.4138954 - 4.560502
Average (Standard dev.)0.0008679341 (±0.10524426)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions400400400
Spacing400400400
CellA=B=C: 355.6 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_14628_msk_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
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Additional map: unsharped

Fileemd_14628_additional_1.map
Annotationunsharped
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Half map: half a

Fileemd_14628_half_map_1.map
Annotationhalf a
Projections & Slices
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Half map: half b

Fileemd_14628_half_map_2.map
Annotationhalf b
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Sample components

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Entire : SARS-CoV-2 Spike protein in complex with the single chain fragmen...

EntireName: SARS-CoV-2 Spike protein in complex with the single chain fragment scFv76Coronavirus spike protein
Components
  • Complex: SARS-CoV-2 Spike protein in complex with the single chain fragment scFv76Coronavirus spike protein
    • Complex: SARS-CoV-2 Spike proteinCoronavirus spike protein
      • Protein or peptide: Spike glycoprotein,Fibritin
    • Complex: scFv76 single chain fragment
      • Protein or peptide: scFv76 single chain fragment
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: SARS-CoV-2 Spike protein in complex with the single chain fragmen...

SupramoleculeName: SARS-CoV-2 Spike protein in complex with the single chain fragment scFv76
type: complex / ID: 1 / Chimera: Yes / Parent: 0 / Macromolecule list: #1-#2
Molecular weightTheoretical: 510 KDa

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Supramolecule #2: SARS-CoV-2 Spike protein

SupramoleculeName: SARS-CoV-2 Spike protein / type: complex / ID: 2 / Chimera: Yes / Parent: 1 / Macromolecule list: #1
Source (natural)Organism: Severe acute respiratory syndrome coronavirus 2

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Supramolecule #3: scFv76 single chain fragment

SupramoleculeName: scFv76 single chain fragment / type: complex / ID: 3 / Chimera: Yes / Parent: 1 / Macromolecule list: #2
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Spike glycoprotein,Fibritin

MacromoleculeName: Spike glycoprotein,Fibritin / type: protein_or_peptide / ID: 1
Details: SARS-CoV-2 Spike HexaPro version. It contain six mutations: F817P, A892P, A899P, A942P, K986P, V987P
Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Enterobacteria phage T4 (virus)
Molecular weightTheoretical: 142.427438 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MFVFLVLLPL VSSQCVNLTT RTQLPPAYTN SFTRGVYYPD KVFRSSVLHS TQDLFLPFFS NVTWFHAIHV SGTNGTKRFD NPVLPFNDG VYFASTEKSN IIRGWIFGTT LDSKTQSLLI VNNATNVVIK VCEFQFCNDP FLGVYYHKNN KSWMESEFRV Y SSANNCTF ...String:
MFVFLVLLPL VSSQCVNLTT RTQLPPAYTN SFTRGVYYPD KVFRSSVLHS TQDLFLPFFS NVTWFHAIHV SGTNGTKRFD NPVLPFNDG VYFASTEKSN IIRGWIFGTT LDSKTQSLLI VNNATNVVIK VCEFQFCNDP FLGVYYHKNN KSWMESEFRV Y SSANNCTF EYVSQPFLMD LEGKQGNFKN LREFVFKNID GYFKIYSKHT PINLVRDLPQ GFSALEPLVD LPIGINITRF QT LLALHRS YLTPGDSSSG WTAGAAAYYV GYLQPRTFLL KYNENGTITD AVDCALDPLS ETKCTLKSFT VEKGIYQTSN FRV QPTESI VRFPNITNLC PFGEVFNATR FASVYAWNRK RISNCVADYS VLYNSASFST FKCYGVSPTK LNDLCFTNVY ADSF VIRGD EVRQIAPGQT GKIADYNYKL PDDFTGCVIA WNSNNLDSKV GGNYNYLYRL FRKSNLKPFE RDISTEIYQA GSTPC NGVE GFNCYFPLQS YGFQPTNGVG YQPYRVVVLS FELLHAPATV CGPKKSTNLV KNKCVNFNFN GLTGTGVLTE SNKKFL PFQ QFGRDIADTT DAVRDPQTLE ILDITPCSFG GVSVITPGTN TSNQVAVLYQ DVNCTEVPVA IHADQLTPTW RVYSTGS NV FQTRAGCLIG AEHVNNSYEC DIPIGAGICA SYQTQTNSPG SASSVASQSI IAYTMSLGAE NSVAYSNNSI AIPTNFTI S VTTEILPVSM TKTSVDCTMY ICGDSTECSN LLLQYGSFCT QLNRALTGIA VEQDKNTQEV FAQVKQIYKT PPIKDFGGF NFSQILPDPS KPSKRSPIED LLFNKVTLAD AGFIKQYGDC LGDIAARDLI CAQKFNGLTV LPPLLTDEMI AQYTSALLAG TITSGWTFG AGPALQIPFP MQMAYRFNGI GVTQNVLYEN QKLIANQFNS AIGKIQDSLS STPSALGKLQ DVVNQNAQAL N TLVKQLSS NFGAISSVLN DILSRLDPPE AEVQIDRLIT GRLQSLQTYV TQQLIRAAEI RASANLAATK MSECVLGQSK RV DFCGKGY HLMSFPQSAP HGVVFLHVTY VPAQEKNFTT APAICHDGKA HFPREGVFVS NGTHWFVTQR NFYEPQIITT DNT FVSGNC DVVIGIVNNT VYDPLQPELD SFKEELDKYF KNHTSPDVDL GDISGINASV VNIQKEIDRL NEVAKNLNES LIDL QELGK YEQGSGYIPE APRDGQAYVR KDGEWVLLST FLGRSLEVLF QGPGHHHHHH HHSAWSHPQF EKGGGSGGGG SGGSA WSHP QFEK

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Macromolecule #2: scFv76 single chain fragment

MacromoleculeName: scFv76 single chain fragment / type: protein_or_peptide / ID: 2 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 28.040947 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: RTMEEVQLLQ SAGGLVQPGG SLRLSCAASG FTVSANYMSW VRQAPGKGLE WVSVIYPGGS TFYADSVKGR FTISRDNSKN TLYLQMNSL RVEDTAVYYC ARDLSVAGAF DIWGQGTLVT VSSGGGGSGG GGSGGGGSEI VLTQSPGTLS LSPGERATLS C RASQSVSS ...String:
RTMEEVQLLQ SAGGLVQPGG SLRLSCAASG FTVSANYMSW VRQAPGKGLE WVSVIYPGGS TFYADSVKGR FTISRDNSKN TLYLQMNSL RVEDTAVYYC ARDLSVAGAF DIWGQGTLVT VSSGGGGSGG GGSGGGGSEI VLTQSPGTLS LSPGERATLS C RASQSVSS SYLAWYQQKP GQAPRLLIYG ASSRATGIPD RFSGSGSGTD FTLTISRLEP EDFAVYYCQQ YGSSPYTFGQ GT KLEIKRA AAGDYKDDDD KHHHHHH

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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: 27 / 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: 7 / Details: PBS
GridModel: Quantifoil / Material: COPPER / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 30 sec. / Pretreatment - Atmosphere: AIR
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TALOS ARCTICA
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 50.0 µm / Illumination mode: OTHER / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm / Nominal defocus max: 2.2 µm / Nominal defocus min: 0.8 µm / Nominal magnification: 120000
Sample stageSpecimen holder model: OTHER / Cooling holder cryogen: NITROGEN
Image recordingFilm or detector model: FEI FALCON III (4k x 4k) / Detector mode: COUNTING / Number grids imaged: 1 / Number real images: 4211 / Average electron dose: 40.0 e/Å2
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 490614
Startup modelType of model: EMDB MAP
EMDB ID:

21452

Initial angle assignmentType: NOT APPLICABLE
Final 3D classificationNumber classes: 1 / Software - Name: cryoSPARC (ver. 3.3.1)
Final angle assignmentType: PROJECTION MATCHING / Software - Name: cryoSPARC (ver. 3.3.1)
Final reconstructionNumber classes used: 1 / Applied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 3.3.1) / Number images used: 87623

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