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- EMDB-33130: Cryo-EM structure of SARS-CoV-2 Delta RBD in complex with BA7054 ... -

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Entry
Database: EMDB / ID: EMD-33130
TitleCryo-EM structure of SARS-CoV-2 Delta RBD in complex with BA7054 and BA7125 fab (local refinement)
Map dataCryo-EM structure of SARS-CoV-2 Delta RBD in complex with BA7054 and BA7125 fab (local refinement)
Sample
  • Complex: Cryo-EM structure of SARS-CoV-2 Delta RBD in complex with BA7054 and BA7125 fab (local refinement)
    • Complex: SARS-CoV-2 Delta RBD
      • Protein or peptide: Spike glycoprotein
    • Complex: BA7054 and BA7125 fab
      • Protein or peptide: BA7054 fab
      • Protein or peptide: BA7054 fab
      • Protein or peptide: BA7125 fab
      • Protein or peptide: BA7125 fab
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 / membrane fusion / receptor-mediated endocytosis of virus by host cell / Attachment and Entry / positive regulation of viral entry into host cell / receptor-mediated virion attachment to host cell / receptor ligand activity / host cell surface receptor binding / symbiont-mediated suppression of host innate immune response / 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 / Coronavirus spike glycoprotein S1, C-terminal / Coronavirus spike glycoprotein S1, C-terminal / Spike glycoprotein, betacoronavirus / Spike glycoprotein, N-terminal domain superfamily / Betacoronavirus spike (S) glycoprotein S1 subunit N-terminal (NTD) domain profile. / Betacoronavirus spike (S) glycoprotein S1 subunit C-terminal (CTD) domain profile. / Spike (S) protein S1 subunit, receptor-binding domain, betacoronavirus / Spike S1 subunit, receptor binding domain superfamily, betacoronavirus ...Spike (S) protein S1 subunit, receptor-binding domain, SARS-CoV-2 / Spike (S) protein S1 subunit, N-terminal domain, SARS-CoV-like / Coronavirus spike glycoprotein S1, C-terminal / Coronavirus spike glycoprotein S1, C-terminal / Spike glycoprotein, betacoronavirus / Spike glycoprotein, N-terminal domain superfamily / Betacoronavirus spike (S) glycoprotein S1 subunit N-terminal (NTD) domain profile. / Betacoronavirus spike (S) glycoprotein S1 subunit C-terminal (CTD) domain profile. / Spike (S) protein S1 subunit, receptor-binding domain, betacoronavirus / Spike S1 subunit, receptor binding domain superfamily, betacoronavirus / Spike glycoprotein S1, N-terminal domain, betacoronavirus-like / Betacoronavirus-like spike glycoprotein S1, N-terminal / Betacoronavirus spike glycoprotein S1, receptor binding / Spike glycoprotein S2, coronavirus, heptad repeat 1 / Spike glycoprotein S2, coronavirus, heptad repeat 2 / Coronavirus spike (S) glycoprotein S2 subunit heptad repeat 1 (HR1) region profile. / Coronavirus spike (S) glycoprotein S2 subunit heptad repeat 2 (HR2) region profile. / Spike glycoprotein S2 superfamily, coronavirus / Spike glycoprotein S2, coronavirus / Coronavirus spike glycoprotein S2
Similarity search - Domain/homology
Biological speciesSevere acute respiratory syndrome coronavirus 2 / Homo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsLiu Z / Liu S
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: Cell Discov / Year: 2023
Title: Biparatopic antibody BA7208/7125 effectively neutralizes SARS-CoV-2 variants including Omicron BA.1-BA.5.
Authors: Yanqun Wang / An Yan / Deyong Song / Chuangchuang Dong / Muding Rao / Yuanzhu Gao / Ruxi Qi / Xiaomin Ma / Qiaoping Wang / Hongguang Xu / Hong Liu / Jing Han / Maoqin Duan / Shuo Liu / ...Authors: Yanqun Wang / An Yan / Deyong Song / Chuangchuang Dong / Muding Rao / Yuanzhu Gao / Ruxi Qi / Xiaomin Ma / Qiaoping Wang / Hongguang Xu / Hong Liu / Jing Han / Maoqin Duan / Shuo Liu / Xiaoping Yu / Mengqi Zong / Jianxia Feng / Jie Jiao / Huimin Zhang / Min Li / Beibei Yu / Yanxia Wang / Fanhao Meng / Xiaodan Ni / Ying Li / Zhenduo Shen / Baiping Sun / Xin Shao / Haifeng Zhao / Yanyan Zhao / Rui Li / Yanan Zhang / Guangying Du / Jun Lu / Chunna You / Hua Jiang / Lu Zhang / Lan Wang / Changlin Dou / Zheng Liu / Jincun Zhao /
Abstract: SARS-CoV-2 Omicron subvariants have demonstrated extensive evasion from monoclonal antibodies (mAbs) developed for clinical use, which raises an urgent need to develop new broad-spectrum mAbs. Here, ...SARS-CoV-2 Omicron subvariants have demonstrated extensive evasion from monoclonal antibodies (mAbs) developed for clinical use, which raises an urgent need to develop new broad-spectrum mAbs. Here, we report the isolation and analysis of two anti-RBD neutralizing antibodies BA7208 and BA7125 from mice engineered to produce human antibodies. While BA7125 showed broadly neutralizing activity against all variants except the Omicron sublineages, BA7208 was potently neutralizing against all tested SARS-CoV-2 variants (including Omicron BA.1-BA.5) except Mu. By combining BA7208 and BA7125 through the knobs-into-holes technology, we generated a biparatopic antibody BA7208/7125 that was able to neutralize all tested circulating SARS-CoV-2 variants. Cryo-electron microscopy structure of these broad-spectrum antibodies in complex with trimeric Delta and Omicron spike indicated that the contact residues are highly conserved and had minimal interactions with mutational residues in RBD of current variants. In addition, we showed that administration of BA7208/7125 via the intraperitoneal, intranasal, or aerosol inhalation route showed potent therapeutic efficacy against Omicron BA.1 and BA.2 in hACE2-transgenic and wild-type mice and, separately, effective prophylaxis. BA7208/7125 thus has the potential to be an effective candidate as an intervention against COVID-19.
History
DepositionMar 26, 2022-
Header (metadata) releaseMar 1, 2023-
Map releaseMar 1, 2023-
UpdateApr 12, 2023-
Current statusApr 12, 2023Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_33130.png

Downloads & links

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Map

FileDownload / File: emd_33130.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCryo-EM structure of SARS-CoV-2 Delta RBD in complex with BA7054 and BA7125 fab (local refinement)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.07 Å/pix.
x 360 pix.
= 385.92 Å		1.07 Å/pix.
x 360 pix.
= 385.92 Å		1.07 Å/pix.
x 360 pix.
= 385.92 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.072 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.4
Minimum - Maximum-2.984186 - 4.987142
Average (Standard dev.)-0.00068734423 (±0.07964035)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 385.92 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Cryo-EM structure of SARS-CoV-2 Delta RBD in complex...

Fileemd_33130_half_map_1.map
AnnotationCryo-EM structure of SARS-CoV-2 Delta RBD in complex with BA7054 and BA7125 fab (local refinement)
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Cryo-EM structure of SARS-CoV-2 Delta RBD in complex...

Fileemd_33130_half_map_2.map
AnnotationCryo-EM structure of SARS-CoV-2 Delta RBD in complex with BA7054 and BA7125 fab (local refinement)
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Cryo-EM structure of SARS-CoV-2 Delta RBD in complex with BA7054 ...

EntireName: Cryo-EM structure of SARS-CoV-2 Delta RBD in complex with BA7054 and BA7125 fab (local refinement)
Components
  • Complex: Cryo-EM structure of SARS-CoV-2 Delta RBD in complex with BA7054 and BA7125 fab (local refinement)
    • Complex: SARS-CoV-2 Delta RBD
      • Protein or peptide: Spike glycoprotein
    • Complex: BA7054 and BA7125 fab
      • Protein or peptide: BA7054 fab
      • Protein or peptide: BA7054 fab
      • Protein or peptide: BA7125 fab
      • Protein or peptide: BA7125 fab

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Supramolecule #1: Cryo-EM structure of SARS-CoV-2 Delta RBD in complex with BA7054 ...

SupramoleculeName: Cryo-EM structure of SARS-CoV-2 Delta RBD in complex with BA7054 and BA7125 fab (local refinement)
type: complex / ID: 1 / Chimera: Yes / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Severe acute respiratory syndrome coronavirus 2

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Supramolecule #2: SARS-CoV-2 Delta RBD

SupramoleculeName: SARS-CoV-2 Delta RBD / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #3: BA7054 and BA7125 fab

SupramoleculeName: BA7054 and BA7125 fab / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #2-#5

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Macromolecule #1: Spike glycoprotein

MacromoleculeName: Spike glycoprotein / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Severe acute respiratory syndrome coronavirus 2
Molecular weightTheoretical: 22.074787 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: TNLCPFGEVF NATRFASVYA WNRKRISNCV ADYSVLYNSA SFSTFKCYGV SPTKLNDLCF TNVYADSFVI RGDEVRQIAP GQTGKIADY NYKLPDDFTG CVIAWNSNNL DSKVGGNYNY RYRLFRKSNL KPFERDISTE IYQAGSKPCN GVEGFNCYFP L QSYGFQPT ...String:
TNLCPFGEVF NATRFASVYA WNRKRISNCV ADYSVLYNSA SFSTFKCYGV SPTKLNDLCF TNVYADSFVI RGDEVRQIAP GQTGKIADY NYKLPDDFTG CVIAWNSNNL DSKVGGNYNY RYRLFRKSNL KPFERDISTE IYQAGSKPCN GVEGFNCYFP L QSYGFQPT NGVGYQPYRV VVLSFELLHA PATVCGPK

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Macromolecule #2: BA7054 fab

MacromoleculeName: BA7054 fab / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.714527 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: EVQLVESGGG VVQPGRSLRL SCAASGFTFS SYAMHWVRQA PGKGLEWVAV ISFDGSNKYY ADSVKGRFTI SRDNSKNTLY LQMNSLRAE DTAVYYCARA SITTTDDGMD VWGQGTTVTV SSASTKGPSV FPLAPSSKST SGGTAALGCL VKDYFPEPVT V SWNSGALT ...String:
EVQLVESGGG VVQPGRSLRL SCAASGFTFS SYAMHWVRQA PGKGLEWVAV ISFDGSNKYY ADSVKGRFTI SRDNSKNTLY LQMNSLRAE DTAVYYCARA SITTTDDGMD VWGQGTTVTV SSASTKGPSV FPLAPSSKST SGGTAALGCL VKDYFPEPVT V SWNSGALT SGVHTFPAVL QSSGLYSLSS VVTVPSSSLG TQTYICNVNH KPSNTKVDKK VEPKSC

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Macromolecule #3: BA7054 fab

MacromoleculeName: BA7054 fab / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.191715 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: DIQMTQSPSS VSASVGDRVT ITCRASQGIS SWLAWYQQKP GKAPKLLIYA ASSLQSGVPS RFSGSGSGTD FTLTISSLQP EDFATYYCQ QANSFPFSFG PGTKVDIKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF YPREAKVQWK VDNALQSGNS Q ESVTEQDS ...String:
DIQMTQSPSS VSASVGDRVT ITCRASQGIS SWLAWYQQKP GKAPKLLIYA ASSLQSGVPS RFSGSGSGTD FTLTISSLQP EDFATYYCQ QANSFPFSFG PGTKVDIKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF YPREAKVQWK VDNALQSGNS Q ESVTEQDS KDSTYSLSST LTLSKADYEK HKVYACEVTH QGLSSPVTKS FNRGEC

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Macromolecule #4: BA7125 fab

MacromoleculeName: BA7125 fab / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.514258 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: EVQLQQWGAG LLKPSETLSL TCAVYGESFS GYYWSWIRQS PGKGLEWIGQ INHSGNTNYN PSLKSRVTMS VDTSKNQFSL KLSSVTAAD TAVYYCAREL GHDYWGQGTL VTVSSASTKG PSVFPLAPSS KSTSGGTAAL GCLVKDYFPE PVTVSWNSGA L TSGVHTFP ...String:
EVQLQQWGAG LLKPSETLSL TCAVYGESFS GYYWSWIRQS PGKGLEWIGQ INHSGNTNYN PSLKSRVTMS VDTSKNQFSL KLSSVTAAD TAVYYCAREL GHDYWGQGTL VTVSSASTKG PSVFPLAPSS KSTSGGTAAL GCLVKDYFPE PVTVSWNSGA L TSGVHTFP AVLQSSGLYS LSSVVTVPSS SLGTQTYICN VNHKPSNTKV DKKVEPKSCD KT

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Macromolecule #5: BA7125 fab

MacromoleculeName: BA7125 fab / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.328883 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: EIVMTQSPGT LSLSPGERAT LSCRASQSIS SSYLAWFQQK PGQAPRLLIY GASSRAPGIP DRFSGSGSGT DFTLTISRLE PEDFAVYYC QQYGDSPLTF GGGTKVDIKR TVAAPSVFIF PPSDEQLKSG TASVVCLLNN FYPREAKVQW KVDNALQSGN S QESVTEQD ...String:
EIVMTQSPGT LSLSPGERAT LSCRASQSIS SSYLAWFQQK PGQAPRLLIY GASSRAPGIP DRFSGSGSGT DFTLTISRLE PEDFAVYYC QQYGDSPLTF GGGTKVDIKR TVAAPSVFIF PPSDEQLKSG TASVVCLLNN FYPREAKVQW KVDNALQSGN S QESVTEQD SKDSTYSLSS TLTLSKADYE KHKVYACEVT HQGLSSPVTK SFNRGEC

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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: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 1.39 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 5.0 µm / Nominal defocus min: 1.2 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 246808
Initial angle assignmentType: OTHER
Final angle assignmentType: OTHER

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