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- EMDB-26202: Cryo-EM structure of antibody TJ5-5 bound to H3 COBRA TJ5 hemaggl... -

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Basic information

Entry
Database: EMDB / ID: EMD-26202
TitleCryo-EM structure of antibody TJ5-5 bound to H3 COBRA TJ5 hemagglutinin
Map dataCOBRA TJ5 complexed with monoclonal antibody TJ5-5
Sample
  • Complex: H3 COBRA HA protein in complex with human antibody TJ5-5
    • Complex: H3 COBRA hemagglutinin protein
      • Protein or peptide: Hemagglutinin
    • Complex: Human antibody TJ5-5
      • Protein or peptide: TJ5-5 heavy chain
      • Protein or peptide: TJ5-5 light chain
KeywordsH3 influenza virus / monoclonal antibody / VIRAL PROTEIN-IMMUNE SYSTEM complex
Function / homology
Function and homology information


viral budding from plasma membrane / clathrin-dependent endocytosis of virus by host cell / host cell surface receptor binding / apical plasma membrane / fusion of virus membrane with host plasma membrane / fusion of virus membrane with host endosome membrane / viral envelope / virion attachment to host cell / host cell plasma membrane / virion membrane
Similarity search - Function
Haemagglutinin, influenzavirus A / Haemagglutinin, HA1 chain, alpha/beta domain superfamily / Haemagglutinin / Haemagglutinin, influenzavirus A/B / Viral capsid/haemagglutinin protein
Similarity search - Domain/homology
Biological speciesHomo sapiens (human) / unidentified influenza virus / Influenza A virus
Methodsingle particle reconstruction / cryo EM / Resolution: 3.41 Å
AuthorsAbbadi NS / Mousa JJ
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)75N93019C00052 United States
CitationJournal: J Virol / Year: 2022
Title: Differential Recognition of Computationally Optimized H3 Hemagglutinin Influenza Vaccine Candidates by Human Antibodies.
Authors: Nada Abbadi / Kaito Nagashima / Alma Pena-Briseno / Ted M Ross / Jarrod J Mousa /
Abstract: Among circulating influenza viruses in humans, H3N2 viruses typically evolve faster than other subtypes and have caused disease in millions of people since emerging in 1968. Computationally optimized ...Among circulating influenza viruses in humans, H3N2 viruses typically evolve faster than other subtypes and have caused disease in millions of people since emerging in 1968. Computationally optimized broadly reactive antigen (COBRA) technology is one strategy to broaden vaccine-elicited antibody responses among influenza subtypes. In this study, we determined the structural integrity of an H3N2 COBRA hemagglutinin (HA), TJ5, and we probed the antigenic profile of several H3N2 COBRA HAs by assessing recognition of these immunogens by human B cells from seasonally vaccinated human subjects. Of three recently described COBRA H3 HA antigens (TJ5, NG2, and J4), we determined that TJ5 and J4 HA proteins recognize pre-existing B cells more effectively than NG2 HA and a wild-type Hong Kong/4801/2014 protein. We also isolated a panel of 12 H3 HA-specific human monoclonal antibodies (MAbs) and identified that most MAbs recognize both wild-type and COBRA HA proteins and have functional activity against a broad panel of H3N2 viruses. Most MAbs target the receptor-binding site, and one MAb targets the HA stem. MAb TJ5-5 recognizes TJ5 and J4 COBRA HA proteins but has poor recognition of NG2 HA, similar to the global B-cell analysis. We determined a 3.4 Å structure via cryo-electron microscopy of Fab TJ5-5 complexed with the H3 COBRA TJ5, which revealed residues important to the differential binding. Overall, these studies determined that COBRA H3 HA proteins have correct antigenic and structural features, and the proteins are recognized by B cells and MAbs isolated from seasonally vaccinated humans. Vaccine development for circulating influenza viruses, particularly for the H3N2 subtype, remains challenging due to consistent antigenic drift. Computationally optimized broadly reactive antigen (COBRA) technology has proven effective for broadening influenza hemagglutinin (HA)-elicited antibody responses compared to wild-type immunogens. Here, we determined the structural features and antigenic profiles of H3 COBRA HA proteins. Two H3 COBRA HA proteins, TJ5 and J4, are better recognized by pre-existing B cells and monoclonal antibodies from the 2017 to 2018 vaccine season compared to COBRA NG2 and a wild-type A/Hong Kong/2014 HA protein. We determined a cryo-electron microscopy (cryo-EM) structure of one MAb that poorly recognizes NG2, MAb TJ5-5, in complex with the TJ5 COBRA HA protein and identified residues critical to MAb recognition. As NG2 is more effective than TJ5 for the recent Hong Kong/2019 virus, these data provide insights into the diminished effectiveness of influenza vaccines across vaccine seasons.
History
DepositionFeb 15, 2022-
Header (metadata) releaseJul 6, 2022-
Map releaseJul 6, 2022-
UpdateOct 23, 2024-
Current statusOct 23, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_26202.png

Downloads & links

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Map

FileDownload / File: emd_26202.map.gz / Format: CCP4 / Size: 512 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCOBRA TJ5 complexed with monoclonal antibody TJ5-5
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.53 Å/pix.
x 512 pix.
= 269.312 Å		0.53 Å/pix.
x 512 pix.
= 269.312 Å		0.53 Å/pix.
x 512 pix.
= 269.312 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.526 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.187
Minimum - Maximum-1.225102 - 2.0893598
Average (Standard dev.)0.0002616593 (±0.06450402)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions512512512
Spacing512512512
CellA=B=C: 269.312 Å
α=β=γ: 90.0 °

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Supplemental data

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Sample components

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Entire : H3 COBRA HA protein in complex with human antibody TJ5-5

EntireName: H3 COBRA HA protein in complex with human antibody TJ5-5
Components
  • Complex: H3 COBRA HA protein in complex with human antibody TJ5-5
    • Complex: H3 COBRA hemagglutinin protein
      • Protein or peptide: Hemagglutinin
    • Complex: Human antibody TJ5-5
      • Protein or peptide: TJ5-5 heavy chain
      • Protein or peptide: TJ5-5 light chain

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Supramolecule #1: H3 COBRA HA protein in complex with human antibody TJ5-5

SupramoleculeName: H3 COBRA HA protein in complex with human antibody TJ5-5
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #2: H3 COBRA hemagglutinin protein

SupramoleculeName: H3 COBRA hemagglutinin protein / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #3
Source (natural)Organism: unidentified influenza virus

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Supramolecule #3: Human antibody TJ5-5

SupramoleculeName: Human antibody TJ5-5 / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: TJ5-5 heavy chain

MacromoleculeName: TJ5-5 heavy chain / type: protein_or_peptide / ID: 1 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 13.487161 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
VQLVQSGAEV KKPGSSVKVS CKASGVTFTY YTISWVRQAP GQGLEWMGGI MPMFGTPNYA QKFQGRVTIT ADEPTSTIYM MLSSLRSED TAVYYCASLG NYESGGYHPY FEYWGHGTLV TVSS

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Macromolecule #2: TJ5-5 light chain

MacromoleculeName: TJ5-5 light chain / type: protein_or_peptide / ID: 2 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 11.114028 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
SVLTQPPSVS GAPGQRVTIS CTGSSSNIGA GYDVHWYQQL PGTAPRLLIY GNSNRPSGVP DRFSGSRSGT SASLAITGLQ AEDEADYYC QSYDNSLSGS GVFGGGTKL

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Macromolecule #3: Hemagglutinin

MacromoleculeName: Hemagglutinin / type: protein_or_peptide / ID: 3 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Influenza A virus
Molecular weightTheoretical: 55.677242 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: NSTATLCLGH HAVPNGTIVK TITNDQIEVT NATELVQSSS TGEICDSPHQ ILDGENCTLI DALLGDPQCD GFQNKKWDLF VERSKAYSN CYPYDVPDYA SLRSLVASSG TLEFNNESFN WTGVTQNGTS SACIRRSNNS FFSRLNWLTH LNFKYPALNV T MPNNEQFD ...String:
NSTATLCLGH HAVPNGTIVK TITNDQIEVT NATELVQSSS TGEICDSPHQ ILDGENCTLI DALLGDPQCD GFQNKKWDLF VERSKAYSN CYPYDVPDYA SLRSLVASSG TLEFNNESFN WTGVTQNGTS SACIRRSNNS FFSRLNWLTH LNFKYPALNV T MPNNEQFD KLYIWGVHHP GTDKDQIFLY AQASGRITVS TKRSQQAVIP NIGSRPRVRN IPSRISIYWT IVKPGDILLI NS TGNLIAP RGYFKIRSGK SSIMRSDAPI GKCNSECITP NGSIPNDKPF QNVNRITYGA CPRYVKQSTL KLATGMRNVP EKQ TRGIFG AIAGFIENGW EGMVDGWYGF RHQNSEGRGQ AADLKSTQAA IDQINGKLNR LIGKTNEKFH QIEKEFSEVE GRIQ DLEKY VEDTKIDLWS YNAELLVALE NQHTIDLTDS EMNKLFEKTK KQLRENAEDM GNGCFKIYHK CDNACIGSIR NGTYD HDVY RDEALNNRFQ I

UniProtKB: Hemagglutinin

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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: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS GLACIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 57.22 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.9 µm

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Image processing

Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

4we8

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.41 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 101267
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE

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