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- PDB-9js4: Cryo-EM structure of neutralizing antibody 8G3 in complex with BA... -

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Basic information

Entry
Database: PDB / ID: 9js4
TitleCryo-EM structure of neutralizing antibody 8G3 in complex with BA.1 RBD
Components
  • Heavy chain of 8G3
  • Light chain of 8G3
  • Spike glycoprotein
KeywordsVIRAL PROTEIN / SARS-CoV-2 / neutralizing antibody / RBD
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 / symbiont-mediated-mediated suppression 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 / symbiont-mediated-mediated suppression of host tetherin activity / Induction of Cell-Cell Fusion / structural constituent of virion / entry receptor-mediated virion attachment to host cell / membrane fusion / Attachment and Entry / host cell endoplasmic reticulum-Golgi intermediate compartment membrane / positive regulation of viral entry into host cell / receptor-mediated virion attachment to host cell / host cell surface receptor binding / symbiont-mediated suppression of host innate immune response / receptor ligand activity / endocytosis involved in viral entry into host cell / 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 / 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. / 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 speciesHomo sapiens (human)
Homo heidelbergensis (Heidelberg man)
Severe acute respiratory syndrome coronavirus
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.8 Å
AuthorsLi, J. / Li, H.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: Proc Natl Acad Sci U S A / Year: 2025
Title: Rapid restoration of potent neutralization activity against the latest Omicron variant JN.1 via AI rational design and antibody engineering.
Authors: Yunji Liao / Hang Ma / Zhenyu Wang / Shusheng Wang / Yang He / Yunsong Chang / Huifang Zong / Haoneng Tang / Lei Wang / Yong Ke / Huiyu Cai / Ping Li / Jian Tang / Hua Chen / Aleksandra ...Authors: Yunji Liao / Hang Ma / Zhenyu Wang / Shusheng Wang / Yang He / Yunsong Chang / Huifang Zong / Haoneng Tang / Lei Wang / Yong Ke / Huiyu Cai / Ping Li / Jian Tang / Hua Chen / Aleksandra Drelich / Bi-Hung Peng / Jason Hsu / Vivian Tat / Chien-Te K Tseng / Jingjing Song / Yunsheng Yuan / Mingyuan Wu / Junjun Liu / Yali Yue / Xiaoju Zhang / Ziqi Wang / Li Yang / Jing Li / Xiaodan Ni / Hongshi Li / Yuning Xiang / Yanlin Bian / Baohong Zhang / Haiyang Yin / Dimiter S Dimitrov / John Gilly / Lei Han / Hua Jiang / Yueqing Xie / Jianwei Zhu /
Abstract: The rapid evolution of the viral genome has led to the continual generation of new variants of SARS-CoV-2. Developing antibody drugs with broad-spectrum and high efficiency is a long-term task. It is ...The rapid evolution of the viral genome has led to the continual generation of new variants of SARS-CoV-2. Developing antibody drugs with broad-spectrum and high efficiency is a long-term task. It is promising but challenging to develop therapeutic neutralizing antibodies (nAbs) through in vitro evolution based on antigen-antibody binding interactions. From an early B cell antibody repertoire, we isolated antibody 8G3 that retains its nonregressive neutralizing activity against Omicron BA.1 and various other strains in vitro. 8G3 protected ACE2 transgenic mice from BA.1 and WA1/2020 virus infection without adverse clinical manifestations and completely cleared viral load in the lungs. Similar to most IGHV3-53 antibodies, the binding sites of 8G3 and ACE2 largely overlap, enabling competition with ACE2 for binding to RBD. By comprehensively considering the binding free energy changes of the antigen-antibody complexes, the biological environment of their interactions, and the evolutionary direction of the antibodies, we were able to select 50 mutants. Among them, 11 were validated by experiments showing better neutralizing activities. Further, a combination of four mutations were identified in 8G3 that increased its neutralization potency against JN.1, the latest Omicron mutant, by approximately 1,500-fold, and one of the mutations led to an improvement in activity against multiple variants to a certain extent. Together, we established a procedure of rapid selection of neutralizing antibodies with potent SARS-CoV-2 neutralization activity. Our results provide a reference for engineering neutralizing antibodies against future SARS-CoV-2 variants and even other pandemic viruses.
History
DepositionSep 30, 2024Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Jan 22, 2025Provider: repository / Type: Initial release
Revision 1.0Jan 22, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Jan 22, 2025Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Jan 22, 2025Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jan 22, 2025Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jan 22, 2025Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jan 22, 2025Data content type: Mask / Data content type: Mask / Provider: repository / Type: Initial release
Revision 1.0Jan 22, 2025Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Feb 26, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
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Revision 1.1Feb 26, 2025Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Database references / Experimental summary / Data content type: EM metadata / EM metadata / EM metadata / Category: citation / citation_author / em_admin
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Light chain of 8G3
B: Heavy chain of 8G3
C: Spike glycoprotein


Theoretical massNumber of molelcules
Total (without water)184,3993
Polymers184,3993
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Antibody Light chain of 8G3


Mass: 23723.164 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Cricetulus griseus (Chinese hamster)
#2: Antibody Heavy chain of 8G3 / Homo sapiens


Mass: 23338.207 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo heidelbergensis (Heidelberg man) / Production host: Cricetulus griseus (Chinese hamster)
#3: Protein Spike glycoprotein / S glycoprotein / E2 / Peplomer protein


Mass: 137337.391 Da / Num. of mol.: 1 / Fragment: RBD domain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Severe acute respiratory syndrome coronavirus
Strain: BA.1, Omicron / Gene: S, 2 / Production host: Cricetulus griseus (Chinese hamster) / References: UniProt: P0DTC2
Has protein modificationY

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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

ComponentName: Cryo-EM structure of neutralizing antibody 8G3 in complex with BA.1 RBD
Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Source (natural)Organism: Severe acute respiratory syndrome coronavirus 2
Source (recombinant)Organism: Cricetulus griseus (Chinese hamster)
Buffer solutionpH: 5.5
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: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 118107 / Symmetry type: POINT
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 43.78 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00243329
ELECTRON MICROSCOPYf_angle_d0.60414534
ELECTRON MICROSCOPYf_chiral_restr0.0441490
ELECTRON MICROSCOPYf_plane_restr0.0058589
ELECTRON MICROSCOPYf_dihedral_angle_d5.4702461

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