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- PDB-7wow: The state 6 of Omicron Spike with bispecific antibody FD01 -

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Basic information

Entry
Database: PDB / ID: 7wow
TitleThe state 6 of Omicron Spike with bispecific antibody FD01
Components
  • 16L9 Fv
  • GW01 Fv
  • Spike glycoproteinSpike protein
KeywordsVIRAL PROTEIN / Omicron / Spike / Bispecific antibody
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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 6.11 Å
AuthorsZhang, X. / Zhan, W.Q. / Chen, Z.G. / Sun, L.
Funding support China, 1items
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, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Nov 30, 2022Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Spike glycoprotein
B: Spike glycoprotein
C: Spike glycoprotein
D: 16L9 Fv
E: GW01 Fv
F: 16L9 Fv
G: GW01 Fv
H: 16L9 Fv
I: GW01 Fv
J: Spike glycoprotein
K: Spike glycoprotein
L: Spike glycoprotein
M: 16L9 Fv
N: GW01 Fv
O: 16L9 Fv
P: GW01 Fv
Q: 16L9 Fv
R: GW01 Fv


Theoretical massNumber of molelcules
Total (without water)1,166,53518
Polymers1,166,53518
Non-polymers00
Water0
1
A: Spike glycoprotein
B: Spike glycoprotein
C: Spike glycoprotein
D: 16L9 Fv
E: GW01 Fv
F: 16L9 Fv
G: GW01 Fv
H: 16L9 Fv
I: GW01 Fv


Theoretical massNumber of molelcules
Total (without water)583,2689
Polymers583,2689
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_5551
2
J: Spike glycoprotein
K: Spike glycoprotein
L: Spike glycoprotein
M: 16L9 Fv
N: GW01 Fv
O: 16L9 Fv
P: GW01 Fv
Q: 16L9 Fv
R: GW01 Fv


Theoretical massNumber of molelcules
Total (without water)583,2689
Polymers583,2689
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein
Spike glycoprotein / Spike protein / S glycoprotein / E2 / Peplomer protein


Mass: 142506.000 Da / Num. of mol.: 6 / Mutation: hexaPro mutations
Source method: isolated from a genetically manipulated source
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.
Source: (gene. exp.) Severe acute respiratory syndrome coronavirus 2
Gene: S, 2 / Variant: omicron / Production host: Homo sapiens (human) / References: UniProt: P0DTC2
#2: Antibody
16L9 Fv


Mass: 25730.025 Da / Num. of mol.: 6
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#3: Antibody
GW01 Fv


Mass: 26186.488 Da / Num. of mol.: 6
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

Component
IDNameTypeEntity IDParent-IDSource
1Omicron Spike with 16L9 and GW01COMPLEXall0RECOMBINANT
2Omicron SpikeCOMPLEX#11RECOMBINANT
316L9 and GW01COMPLEX#2-#31RECOMBINANT
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
12Severe acute respiratory syndrome coronavirus 22697049
23Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
12Homo sapiens (human)9606
23Homo sapiens (human)9606
Buffer solutionpH: 8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2500 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 58 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.17.1_3660: / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 6.11 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 71568 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00170970
ELECTRON MICROSCOPYf_angle_d0.39996578
ELECTRON MICROSCOPYf_dihedral_angle_d12.46525186
ELECTRON MICROSCOPYf_chiral_restr0.0410760
ELECTRON MICROSCOPYf_plane_restr0.00412566

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