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- EMDB-61766: Cryo-EM structure of neutralizing antibody 8G3 in complex with BA... -

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Entry
Database: EMDB / ID: EMD-61766
TitleCryo-EM structure of neutralizing antibody 8G3 in complex with BA.1 RBD
Map data
Sample
  • Complex: Cryo-EM structure of neutralizing antibody 8G3 in complex with BA.1 RBD
    • Protein or peptide: Light chain of 8G3
    • Protein or peptide: Heavy chain of 8G3
    • Protein or peptide: Spike glycoprotein
KeywordsSARS-CoV-2 / neutralizing antibody / RBD / VIRAL PROTEIN
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 speciesSevere acute respiratory syndrome coronavirus 2 / Homo sapiens (human) / Homo heidelbergensis (Heidelberg man) / Severe acute respiratory syndrome coronavirus
Methodsingle particle reconstruction / cryo EM / Resolution: 3.8 Å
AuthorsLi J / Li H
Funding support China, 1 items
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, 2024-
Header (metadata) releaseJan 22, 2025-
Map releaseJan 22, 2025-
UpdateFeb 26, 2025-
Current statusFeb 26, 2025Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_61766.png

Downloads & links

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Map

FileDownload / File: emd_61766.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
1.1 Å/pix.
x 400 pix.
= 440. Å		1.1 Å/pix.
x 400 pix.
= 440. Å		1.1 Å/pix.
x 400 pix.
= 440. Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.1 Å
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Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.6
Minimum - Maximum-1.5962365 - 2.4498417
Average (Standard dev.)-0.0021914984 (±0.03618098)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions400400400
Spacing400400400
CellA=B=C: 440.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_61766_msk_1.map
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Half map: #2

Fileemd_61766_half_map_1.map
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Half map: #1

Fileemd_61766_half_map_2.map
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Sample components

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Entire : Cryo-EM structure of neutralizing antibody 8G3 in complex with BA...

EntireName: Cryo-EM structure of neutralizing antibody 8G3 in complex with BA.1 RBD
Components
  • Complex: Cryo-EM structure of neutralizing antibody 8G3 in complex with BA.1 RBD
    • Protein or peptide: Light chain of 8G3
    • Protein or peptide: Heavy chain of 8G3
    • Protein or peptide: Spike glycoprotein

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Supramolecule #1: Cryo-EM structure of neutralizing antibody 8G3 in complex with BA...

SupramoleculeName: Cryo-EM structure of neutralizing antibody 8G3 in complex with BA.1 RBD
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Severe acute respiratory syndrome coronavirus 2

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Macromolecule #1: Light chain of 8G3

MacromoleculeName: Light chain of 8G3 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.723164 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString: DIQLTQSPSS LSASVGDRVT ITCQASQDIS NYLNWYQQKP GKAPKLLIYD ASNLETGVPS RFSASGSGTD FTFTISSLQP EDIATYYCQ HYDDLPNLPP TFGGGTKVEI KRTVAAPSVF IFPPSDEQLK SGTASVVCLL NNFYPREAKV QWKVDNALQS G NSQESVTE ...String:
DIQLTQSPSS LSASVGDRVT ITCQASQDIS NYLNWYQQKP GKAPKLLIYD ASNLETGVPS RFSASGSGTD FTFTISSLQP EDIATYYCQ HYDDLPNLPP TFGGGTKVEI KRTVAAPSVF IFPPSDEQLK SGTASVVCLL NNFYPREAKV QWKVDNALQS G NSQESVTE QDSKDSTYSL SSTLTLSKAD YEKHKVYACE VTHQGLSSPV TKSFNRGEC

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Macromolecule #2: Heavy chain of 8G3

MacromoleculeName: Heavy chain of 8G3 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo heidelbergensis (Heidelberg man)
Molecular weightTheoretical: 23.338207 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString: QVQLVESGGG LVQPGGSLRL SCAASGLTVS SNYMNWVRQA PGKGLEWVSV IYPGGTTYYA DSVKGRFTIS RHNSKNTLYL EMNSLRPED TAVYYCARPI YGGNAGMDVW GQGTTVTVSS ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS W NSGALTSG ...String:
QVQLVESGGG LVQPGGSLRL SCAASGLTVS SNYMNWVRQA PGKGLEWVSV IYPGGTTYYA DSVKGRFTIS RHNSKNTLYL EMNSLRPED TAVYYCARPI YGGNAGMDVW GQGTTVTVSS ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS W NSGALTSG VHTFPAVLQS SGLYSLSSVV TVPSSSLGTQ TYICNVNHKP SNTKVDKKVE PKSC

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Macromolecule #3: Spike glycoprotein

MacromoleculeName: Spike glycoprotein / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Severe acute respiratory syndrome coronavirus / Strain: BA.1, Omicron
Molecular weightTheoretical: 137.337391 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString: VNLTTRTQLP PAYTNSFTRG VYYPDKVFRS SVLHSTQDLF LPFFSNVTWF HVIHVSGTNG TKRFDNPVLP FNDGVYFASI EKSNIIRGW IFGTTLDSKT QSLLIVNNAT NVVIKVCEFQ FCNDPFLGVY DHKNNKSWME SEFRVYSSAN NCTFEYVSQP F LMDLEGKQ ...String:
VNLTTRTQLP PAYTNSFTRG VYYPDKVFRS SVLHSTQDLF LPFFSNVTWF HVIHVSGTNG TKRFDNPVLP FNDGVYFASI EKSNIIRGW IFGTTLDSKT QSLLIVNNAT NVVIKVCEFQ FCNDPFLGVY DHKNNKSWME SEFRVYSSAN NCTFEYVSQP F LMDLEGKQ GNFKNLREFV FKNIDGYFKI YSKHTPIIVR EPEDLPQGFS ALEPLVDLPI GINITRFQTL LALHRSYLTP GD SSSGWTA GAAAYYVGYL QPRTFLLKYN ENGTITDAVD CALDPLSETK CTLKSFTVEK GIYQTSNFRV QPTESIVRFP NIT NLCPFD EVFNATRFAS VYAWNRKRIS NCVADYSVLY NLAPFFTFKC YGVSPTKLND LCFTNVYADS FVIRGDEVRQ IAPG QTGNI ADYNYKLPDD FTGCVIAWNS NKLDSKVSGN YNYLYRLFRK SNLKPFERDI STEIYQAGNK PCNGVAGFNC YFPLR SYSF RPTYGVGHQP YRVVVLSFEL LHAPATVCGP KKSTNLVKNK CVNFNFNGLK GTGVLTESNK KFLPFQQFGR DIADTT DAV RDPQTLEILD ITPCSFGGVS VITPGTNTSN QVAVLYQGVN CTEVPVAIHA DQLTPTWRVY STGSNVFQTR AGCLIGA EY VNNSYECDIP IGAGICASYQ TQTKSHGSAS SVASQSIIAY TMSLGAENSV AYSNNSIAIP TNFTISVTTE ILPVSMTK T SVDCTMYICG DSTECSNLLL QYGSFCTQLK RALTGIAVEQ DKNTQEVFAQ VKQIYKTPPI KYFGGFNFSQ ILPDPSKPS KRSPIEDLLF NKVTLADAGF IKQYGDCLGD IAARDLICAQ KFKGLTVLPP LLTDEMIAQY TSALLAGTIT SGWTFGAGPA LQIPFPMQM AYRFNGIGVT QNVLYENQKL IANQFNSAIG KIQDSLSSTP SALGKLQDVV NHNAQALNTL VKQLSSKFGA I SSVLNDIF SRLDPPEAEV QIDRLITGRL QSLQTYVTQQ LIRAAEIRAS ANLAATKMSE CVLGQSKRVD FCGKGYHLMS FP QSAPHGV VFLHVTYVPA QEKNFTTAPA ICHDGKAHFP REGVFVSNGT HWFVTQRNFY EPQIITTDNT FVSGNCDVVI GIV NNTVYD PLQPELDSFK EELDKYFKNH TSPDVDLGDI SGINASVVNI QKEIDRLNEV AKNLNESLID LQELGKYEQG YIPE APRDG QAYVRKDGEW VLLSTFLAHH HHHHHHHH

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: 5.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k 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: 2.0 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.8 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 118107
Initial angle assignmentType: PROJECTION MATCHING
Final angle assignmentType: PROJECTION MATCHING
FSC plot (resolution estimation)

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