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- EMDB-32657: The state 3 of Omicron Spike with bispecific antibody FD01 -

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Basic information

Entry
Database: EMDB / ID: EMD-32657
TitleThe state 3 of Omicron Spike with bispecific antibody FD01
Map data
Sample
  • Complex: Omicron Spike with 16L9 and GW01
    • Complex: Omicron Spike
      • Protein or peptide: Spike glycoproteinSpike protein
    • Complex: 16L9 and GW01
      • Protein or peptide: 16L9 Fv
      • Protein or peptide: GW01 Fv
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
Function / homology
Function and homology information


Maturation of spike protein / Translation of Structural Proteins / Virion Assembly and Release / suppression by virus of host tetherin activity / host cell endoplasmic reticulum-Golgi intermediate compartment membrane / Attachment and Entry / viral life cycle / membrane fusion / receptor-mediated endocytosis of virus by host cell / positive regulation of viral entry into host cell ...Maturation of spike protein / Translation of Structural Proteins / Virion Assembly and Release / suppression by virus of host tetherin activity / host cell endoplasmic reticulum-Golgi intermediate compartment membrane / Attachment and Entry / viral life cycle / membrane fusion / receptor-mediated endocytosis of virus by host cell / positive regulation of viral entry into host cell / receptor-mediated virion attachment to host cell / host cell surface receptor binding / fusion of virus membrane with host plasma membrane / fusion of virus membrane with host endosome membrane / suppression by virus of host type I interferon-mediated signaling pathway / viral envelope / viral entry into host cell / SARS-CoV-2 activates/modulates innate and adaptive immune responses / host cell plasma membrane / virion membrane / membrane / identical protein binding
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 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 speciesSevere acute respiratory syndrome coronavirus 2 / Homo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.91 Å
AuthorsZhang X / Zhan WQ / Chen ZG / Sun L
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)81900729 China
CitationJournal: Cell Discov / Year: 2022
Title: Combating the SARS-CoV-2 Omicron (BA.1) and BA.2 with potent bispecific antibodies engineered from non-Omicron neutralizing antibodies.
Authors: Yingdan Wang / Xiang Zhang / Yunping Ma / Yanqun Wang / Wuqiang Zhan / Qinwen Zheng / Meng Zhang / Ping Ji / Mei Liu / Qianying Liu / Tingting Sun / Tongyu Zhu / Yumei Wen / Lei Sun / Jincun ...Authors: Yingdan Wang / Xiang Zhang / Yunping Ma / Yanqun Wang / Wuqiang Zhan / Qinwen Zheng / Meng Zhang / Ping Ji / Mei Liu / Qianying Liu / Tingting Sun / Tongyu Zhu / Yumei Wen / Lei Sun / Jincun Zhao / Fan Wu / Zhenguo Chen / Jinghe Huang /
Abstract: The highly mutated and transmissible Omicron (BA.1) and its more contagious lineage BA.2 have provoked serious concerns over their decreased sensitivity to the current COVID-19 vaccines and evasion ...The highly mutated and transmissible Omicron (BA.1) and its more contagious lineage BA.2 have provoked serious concerns over their decreased sensitivity to the current COVID-19 vaccines and evasion from most anti-SARS-CoV-2 neutralizing antibodies (NAbs). In this study, we explored the possibility of combating the Omicron and BA.2 by constructing bispecific antibodies based on non-Omicron NAbs. We engineered 10 IgG-like bispecific antibodies with non-Omicron NAbs named GW01, 16L9, 4L12, and REGN10987 by fusing the single-chain variable fragments (scFvs) of two antibodies through a linker and then connecting them to the Fc region of IgG1. Surprisingly, 8 out of 10 bispecific antibodies showed high binding affinities to the Omicron receptor-binding domain (RBD) and exhibited extreme breadth and potency against pseudotyped SARS-CoV-2 variants of concern (VOCs) including Omicron and BA.2, with geometric mean of 50% inhibitory concentration (GM IC) values ranging from 4.5 ng/mL to 103.94 ng/mL, as well as the authentic BA.1.1. Six bispecific antibodies containing the cross-NAb GW01 not only neutralized Omicron and BA.2, but also neutralized the sarbecoviruses including SARS-CoV and SARS-related coronaviruses (SARSr-CoVs) RS3367 and WIV1, with GM IC ranging from 11.6 ng/mL to 103.9 ng/mL. Mapping analyses of 42 spike (S) variant single mutants of Omicron and BA.2 elucidated that these bispecific antibodies accommodated the S371L/F mutations, which were resistant to most of the non-Omicron NAbs. A cryo-electron microscopy (cryo-EM) structure study of the representative bispecific antibody GW01-16L9 (FD01) in its native full-length IgG form in complex with the Omicron S trimer revealed 5 distinct trimers and one novel trimer dimer conformation. 16L9 scFv binds the receptor-binding motif (RBM), while GW01 scFv binds a epitope outside the RBM. Two scFvs of the bispecific antibody synergistically induced the RBD-down conformation into 3 RBD-up conformation, improved the affinity between IgG and the Omicron RBD, induced the formation of trimer dimer, and inhibited RBD binding to ACE2. The trimer dimer conformation might induce the aggregation of virions and contribute to the neutralization ability of FD01. These novel bispecific antibodies are strong candidates for the treatment and prevention of infection with the Omicron, BA.2, VOCs, and other sarbecoviruses. Engineering bispecific antibodies based on non-Omicron NAbs could turn the majority of NAbs into a powerful arsenal to aid the battle against the pandemic.
History
DepositionJan 22, 2022-
Header (metadata) releaseNov 30, 2022-
Map releaseNov 30, 2022-
UpdateNov 30, 2022-
Current statusNov 30, 2022Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

Downloads & links

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Map

FileDownload / File: emd_32657.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.06 Å/pix.
x 320 pix.
= 340.48 Å
1.06 Å/pix.
x 320 pix.
= 340.48 Å
1.06 Å/pix.
x 320 pix.
= 340.48 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.064 Å
Density
Contour LevelBy AUTHOR: 0.02
Minimum - Maximum-0.00168814 - 1.588864
Average (Standard dev.)0.0019622045 (±0.02837705)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 340.48 Å
α=β=γ: 90.0 °

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Supplemental data

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Sample components

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Entire : Omicron Spike with 16L9 and GW01

EntireName: Omicron Spike with 16L9 and GW01
Components
  • Complex: Omicron Spike with 16L9 and GW01
    • Complex: Omicron Spike
      • Protein or peptide: Spike glycoproteinSpike protein
    • Complex: 16L9 and GW01
      • Protein or peptide: 16L9 Fv
      • Protein or peptide: GW01 Fv
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: Omicron Spike with 16L9 and GW01

SupramoleculeName: Omicron Spike with 16L9 and GW01 / type: complex / Chimera: Yes / ID: 1 / Parent: 0 / Macromolecule list: #1-#3

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Supramolecule #2: Omicron Spike

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

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Supramolecule #3: 16L9 and GW01

SupramoleculeName: 16L9 and GW01 / type: complex / Chimera: Yes / ID: 3 / Parent: 1 / Macromolecule list: #2-#3
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Spike glycoprotein

MacromoleculeName: Spike glycoprotein / type: protein_or_peptide / ID: 1
Details: residues 682-685 are substitution at furin cleavage site. T4 fibritin trimerization motif, twin strep II tag and 8-His were introduced at C-terminal.
Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Severe acute respiratory syndrome coronavirus 2
Molecular weightTheoretical: 142.506 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MFVFLVLLPL VSSQCVNLTT RTQLPPAYTN SFTRGVYYPD KVFRSSVLHS TQDLFLPFFS NVTWFHVISG TNGTKRFDNP VLPFNDGVY FASIEKSNII RGWIFGTTLD SKTQSLLIVN NATNVVIKVC EFQFCNDPFL DHKNNKSWME SEFRVYSSAN N CTFEYVSQ ...String:
MFVFLVLLPL VSSQCVNLTT RTQLPPAYTN SFTRGVYYPD KVFRSSVLHS TQDLFLPFFS NVTWFHVISG TNGTKRFDNP VLPFNDGVY FASIEKSNII RGWIFGTTLD SKTQSLLIVN NATNVVIKVC EFQFCNDPFL DHKNNKSWME SEFRVYSSAN N CTFEYVSQ PFLMDLEGKQ GNFKNLREFV FKNIDGYFKI YSKHTPIIVR EPEDLPQGFS ALEPLVDLPI GINITRFQTL LA LHRSYLT PGDSSSGWTA GAAAYYVGYL QPRTFLLKYN ENGTITDAVD CALDPLSETK CTLKSFTVEK GIYQTSNFRV QPT ESIVRF PNITNLCPFD EVFNATRFAS VYAWNRKRIS NCVADYSVLY NLAPFFTFKC YGVSPTKLND LCFTNVYADS FVIR GDEVR QIAPGQTGNI ADYNYKLPDD FTGCVIAWNS NKLDSKVSGN YNYLYRLFRK SNLKPFERDI STEIYQAGNK PCNGV AGFN CYFPLRSYSF RPTYGVGHQP YRVVVLSFEL LHAPATVCGP KKSTNLVKNK CVNFNFNGLK GTGVLTESNK KFLPFQ QFG RDIADTTDAV RDPQTLEILD ITPCSFGGVS VITPGTNTSN QVAVLYQGVN CTEVPVAIHA DQLTPTWRVY STGSNVF QT RAGCLIGAEY VNNSYECDIP IGAGICASYQ TQTKSHGSAS SVASQSIIAY TMSLGAENSV AYSNNSIAIP TNFTISVT T EILPVSMTKT SVDCTMYICG DSTECSNLLL QYGSFCTQLK RALTGIAVEQ DKNTQEVFAQ VKQIYKTPPI KYFGGFNFS QILPDPSKPS KRSPIEDLLF NKVTLADAGF IKQYGDCLGD IAARDLICAQ KFKGLTVLPP LLTDEMIAQY TSALLAGTIT SGWTFGAGP ALQIPFPMQM AYRFNGIGVT QNVLYENQKL IANQFNSAIG KIQDSLSSTP SALGKLQDVV NHNAQALNTL V KQLSSKFG AISSVLNDIF SRLDPPEAEV 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 EWVFLSTFLS GLEVLFQGPG GWSHPQFEKG GGSGGGSGGS AWSHPQFEKG GSHHH HHHH H

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Macromolecule #2: 16L9 Fv

MacromoleculeName: 16L9 Fv / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 25.730025 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: QSVLTQPPSA SGSPGQSVTI SCTGTSSDFG GYNSVSWYQQ HPGKAPKLMI YEVSKRPSGV PDRFSGSKSG NTASLTVSGL QAEDEADYY CSSYAGSNNF DVFGTGTKVT VLGGGGSGGG GSGGGGSEVQ LVESGGGLIQ PGGSLRLSCA ASGFTVSSNY M SWVRQAPG ...String:
QSVLTQPPSA SGSPGQSVTI SCTGTSSDFG GYNSVSWYQQ HPGKAPKLMI YEVSKRPSGV PDRFSGSKSG NTASLTVSGL QAEDEADYY CSSYAGSNNF DVFGTGTKVT VLGGGGSGGG GSGGGGSEVQ LVESGGGLIQ PGGSLRLSCA ASGFTVSSNY M SWVRQAPG KGLEWVSVIY SGGSTYYADS VKGRFTISRD NSENTLYLQM NSLRAEDTAV YYCARGEIQP YYYYGMDVWG QG TTVTVSS

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Macromolecule #3: GW01 Fv

MacromoleculeName: GW01 Fv / type: protein_or_peptide / ID: 3 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 26.186488 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: QSVLTQPPSA SGTPGQRVTI SCSGSSSNIG SNTVNWYQQL PGTAPKLLIY SNNQRPSGVP DRFSGSKSGT SASLAISGLQ SEDEADYYC AAWDDSLNWV FGGGTKLTVL GGGGSGGGGS GGGGSEVQLV ESGGGVVQPG GSLRLSCAAS GFRFDDHAMH W VRQAPGKG ...String:
QSVLTQPPSA SGTPGQRVTI SCSGSSSNIG SNTVNWYQQL PGTAPKLLIY SNNQRPSGVP DRFSGSKSGT SASLAISGLQ SEDEADYYC AAWDDSLNWV FGGGTKLTVL GGGGSGGGGS GGGGSEVQLV ESGGGVVQPG GSLRLSCAAS GFRFDDHAMH W VRQAPGKG LEWVSVISGD GGSTYYADSV KGRFSISRDD SKNSLYLQMN SLRTEDTALY YCAKDRSYGP PDVFNYEYGM DV WGQGTTV TVSS

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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: 21 / 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

BufferpH: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.2 µm
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 58.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Initial angle assignmentType: PROJECTION MATCHING
Final angle assignmentType: PROJECTION MATCHING
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.91 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 74415
FSC plot (resolution estimation)

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