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- EMDB-39646: the complex structure of the H4B6 Fab with the RBD of Omicron BA.... -

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Basic information

Entry
Database: EMDB / ID: EMD-39646
Titlethe complex structure of the H4B6 Fab with the RBD of Omicron BA.5 S protein
Map data
Sample
  • Complex: the complex structure of the H4B6 Fab with the RBD of Omicron BA.5 S protein
    • Protein or peptide: H4B6 Fab's heavy chain
    • Protein or peptide: H4B6 Fab's light chain
    • Protein or peptide: Spike protein S2'
Keywordsantibody / VIRAL PROTEIN/IMMUNE SYSTEM / VIRAL PROTEIN-IMMUNE SYSTEM complex
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 / entry receptor-mediated virion attachment to host cell ...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 / entry receptor-mediated virion attachment to host cell / host cell endoplasmic reticulum-Golgi intermediate compartment membrane / 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 / identical protein binding / membrane / 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 speciesHomo sapiens (human) / Severe acute respiratory syndrome coronavirus 2
Methodsingle particle reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsXia LY / Zhang YY / Zhou Q / Yan RH
Funding support1 items
OrganizationGrant numberCountry
Not funded
CitationJournal: Emerg Microbes Infect / Year: 2024
Title: A novel bispecific antibody targeting two overlapping epitopes in RBD improves neutralizing potency and breadth against SARS-CoV-2.
Authors: Hancong Sun / Lingyun Xia / Jianhua Li / Yuanyuan Zhang / Guanying Zhang / Ping Huang / Xingxing Wang / Yue Cui / Ting Fang / Pengfei Fan / Qiang Zhou / Xiangyang Chi / Changming Yu /
Abstract: SARS-CoV-2 has been evolving into a large number of variants, including the highly pathogenic Delta variant, and the currently prevalent Omicron subvariants with extensive evasion capability, which ...SARS-CoV-2 has been evolving into a large number of variants, including the highly pathogenic Delta variant, and the currently prevalent Omicron subvariants with extensive evasion capability, which raises an urgent need to develop new broad-spectrum neutralizing antibodies. Herein, we engineer two IgG-(scFv) form bispecific antibodies with overlapping epitopes (bsAb1) or non-overlapping epitopes (bsAb2). Both bsAbs are significantly superior to the parental monoclonal antibodies in terms of their antigen-binding and virus-neutralizing activities against all tested circulating SARS-CoV-2 variants including currently dominant JN.1. The bsAb1 can efficiently neutralize all variants insensitive to parental monoclonal antibodies or the cocktail with IC lower than 20 ng/mL, even slightly better than bsAb2. Furthermore, the cryo-EM structures of bsAb1 in complex with the Omicron spike protein revealed that bsAb1 with overlapping epitopes effectively locked the S protein, which accounts for its conserved neutralization against Omicron variants. The bispecific antibody strategy engineered from overlapping epitopes provides a novel solution for dealing with viral immune evasion.
History
DepositionApr 1, 2024-
Header (metadata) releaseJul 31, 2024-
Map releaseJul 31, 2024-
UpdateJul 31, 2024-
Current statusJul 31, 2024Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_39646.png

Downloads & links

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Map

FileDownload / File: emd_39646.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.09 Å/pix.
x 400 pix.
= 434.8 Å		1.09 Å/pix.
x 400 pix.
= 434.8 Å		1.09 Å/pix.
x 400 pix.
= 434.8 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.087 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.4
Minimum - Maximum-5.3158436 - 6.83167
Average (Standard dev.)-0.000733213 (±0.041245967)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions400400400
Spacing400400400
CellA=B=C: 434.80002 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_39646_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_39646_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 : the complex structure of the H4B6 Fab with the RBD of Omicron BA....

EntireName: the complex structure of the H4B6 Fab with the RBD of Omicron BA.5 S protein
Components
  • Complex: the complex structure of the H4B6 Fab with the RBD of Omicron BA.5 S protein
    • Protein or peptide: H4B6 Fab's heavy chain
    • Protein or peptide: H4B6 Fab's light chain
    • Protein or peptide: Spike protein S2'

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Supramolecule #1: the complex structure of the H4B6 Fab with the RBD of Omicron BA....

SupramoleculeName: the complex structure of the H4B6 Fab with the RBD of Omicron BA.5 S protein
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: H4B6 Fab's heavy chain

MacromoleculeName: H4B6 Fab's heavy chain / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 76.157969 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: EVQLVESGGD LVQPGGSLRL SCAASGFIVS RNYMSWVRQA PGKGLEWVSS IYSGGSTFYA GSVKGRFTIS RDNSKNTLYL QMNSLRAED TAIYYCARDI PRHGGDSWGQ GTLVTVSSAS TKGPSVFPLA PSSKSTSGGT AALGCLVKDY FPEPVTVSWN S GALTSGVH ...String:
EVQLVESGGD LVQPGGSLRL SCAASGFIVS RNYMSWVRQA PGKGLEWVSS IYSGGSTFYA GSVKGRFTIS RDNSKNTLYL QMNSLRAED TAIYYCARDI PRHGGDSWGQ GTLVTVSSAS TKGPSVFPLA PSSKSTSGGT AALGCLVKDY FPEPVTVSWN S GALTSGVH TFPAVLQSSG LYSLSSVVTV PSSSLGTQTY ICNVNHKPSN TKVDKKVEPK SCDKTHTCPP CPAPELLGGP SV FLFPPKP KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN STYRVVSVLT VLHQDWLNGK EYK CKVSNK ALPAPIEKTI SKAKGQPREP QVYTLPPSRD ELTKNQVSLT CLVKGFYPSD IAVEWESNGQ PENNYKTTPP VLDS DGSFF LYSKLTVDKS RWQQGNVFSC SVMHEALHNH YTQKSLSLSP GKGGGGSGGG GSGGGGEVQL VESGGGLVQP GWSLR LSCV VSGLKFDDFA MHWVRQVPGK GLEWVSGLNW NGDNVAFADS VKGRFTISRD NAENSLYLQM NNLRPEDTAF YYCAKD SYY DILTGYSGAF DMWGQGTMVT VSSGGGGSGG GGSGGGGAIR MTQSPATLSL SPGERATLSC RASQSVHNYL AWYQQKP GQ APRLLFYDAS NRATGIPARF SASASGTDST LTISSLEPED FAVYYCQQRR NGYSFGQGTK VEIKR

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Macromolecule #2: H4B6 Fab's light chain

MacromoleculeName: H4B6 Fab's light chain / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.574154 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: AIRMTQSPAS LSASIGDRVT ITCQASQDIN KYLNWYQQKP GKAPRLLIYD ASNLETGVPS RFSGSGSGTD FTFTISSLQP EDIATYYCQ QYDNLPITFG QGTRLEIKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF YPREAKVQWK VDNALQSGNS Q ESVTEQDS ...String:
AIRMTQSPAS LSASIGDRVT ITCQASQDIN KYLNWYQQKP GKAPRLLIYD ASNLETGVPS RFSGSGSGTD FTFTISSLQP EDIATYYCQ QYDNLPITFG QGTRLEIKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF YPREAKVQWK VDNALQSGNS Q ESVTEQDS KDSTYSLSST LTLSKADYEK HKVYACEVTH QGLSSPVTKS FNRGEC

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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 2 / Strain: Omicron/BA.5
Molecular weightTheoretical: 124.212977 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: AYTNSFTRGV YYPDKVFRSS VLHSTQDLFL PFFSNVTWFH AIHVSGTNGT KRFDNPVLPF NDGVYFASTE KSNIIRGWIF GTTLDSKTQ SLLIVNNATN VVIKVCEFQF CNDPFLGVYY HKNNKSWMES DFRVYSSANN CTFEYVSQPF LMDLEGKQGN F KNLREFVF ...String:
AYTNSFTRGV YYPDKVFRSS VLHSTQDLFL PFFSNVTWFH AIHVSGTNGT KRFDNPVLPF NDGVYFASTE KSNIIRGWIF GTTLDSKTQ SLLIVNNATN VVIKVCEFQF CNDPFLGVYY HKNNKSWMES DFRVYSSANN CTFEYVSQPF LMDLEGKQGN F KNLREFVF KNIDGYFKIY SKHTPINLVR DLPQGFSALE PLVDLPIGIN ITRFQTLLAL HRSYLTPGDS SSGWTAGAAA YY VGYLQPR TFLLKYNENG TITDAVDCAL DPLSETKCTL KSFTVEKGIY QTSNFRVQPT ESIVRFPNIT NLCPFDEVFN ATR FASVYA WNRKRISNCV ADYSVLYNFA PFFAFKCYGV SPTKLNDLCF TNVYADSFVI RGNEVSQIAP GQTGNIADYN YKLP DDFTG CVIAWNSNKL DSKVGGNYNY RYRLFRKSNL KPFERDISTE IYQAGNKPCN GVAGVNCYFP LQSYGFRPTY GVGHQ PYRV VVLSFELLHA PATVCGPKKS TNLVKNKCVN FNFNGLTGTG VLTESNKKFL PFQQFGRDIA DTTDAVRDPQ TLEILD ITP CSFGGVSVIT PGTNTSNQVA VLYQGVNCTE VPVAIHADQL TPTWRVYSTG SNVFQTRAGC LIGAEYVNSS YECDIPI GA GICASYQTQT NSPRRARSVA SQSIIAYTMS LGAENSVAYS NNSIAIPTNF TISVTTEILP VSMTKTSVDC TMYICGDS T ECSNLLLQYG SFCTQLKRAL TGIAVEQDKN TQEVFAQVKQ IYKTPPIKYF GGFNFSQILP DPSKPSKRSP IEDLLFNKV TLADAGFIKQ YGDCLGDIAA RDLICAQKFN GLTVLPPLLT DEMIAQYTSA LLAGTITSGW TFGAGPALQI PFPMQMAYRF NGIGVTQNV LYENQKLIAN QFNSAIGKIQ DSLSSTPSAL GKLQDVVNHN AQALNTLVKQ LSSKFGAISS VLNDILSRLD P PEAEVQID RLITGRLQSL QTYVTQQLIR AAEIRASANL AATKMSECVL GQSKRVDFCG KGYHLMSFPQ SAPHGVVFLH VT YVPAQEK NFTTAPAICH DGKAHFPREG VFVSNGTHWF VTQRNFYEPQ IITTDNTFVS GNCDVVIGIV NNTVYDPLQP ELD

UniProtKB: Spike glycoprotein

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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

BufferpH: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.2 µm / Nominal defocus min: 1.2 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. v4) / Number images used: 368678
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION

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