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- PDB-7tz5: Cryo-EM structure of antibody TJ5-5 bound to H3 COBRA TJ5 hemaggl... -

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Basic information

Entry
Database: PDB / ID: 7tz5
TitleCryo-EM structure of antibody TJ5-5 bound to H3 COBRA TJ5 hemagglutinin
Components
  • Hemagglutinin
  • TJ5-5 heavy chain
  • TJ5-5 light chain
KeywordsVIRAL PROTEIN/IMMUNE SYSTEM / H3 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 / membrane => GO:0016020 / 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)
Influenza A virus
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.41 Å
AuthorsAbbadi, N.S. / Mousa, J.J.
Funding support United States, 1items
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, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 6, 2022Provider: repository / Type: Initial release
Revision 1.1Aug 24, 2022Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Sep 7, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.3Sep 21, 2022Group: Database references / Category: citation / citation_author
Item: _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
H: TJ5-5 heavy chain
I: TJ5-5 heavy chain
J: TJ5-5 heavy chain
L: TJ5-5 light chain
M: TJ5-5 light chain
N: TJ5-5 light chain
A: Hemagglutinin
B: Hemagglutinin
C: Hemagglutinin


Theoretical massNumber of molelcules
Total (without water)240,8359
Polymers240,8359
Non-polymers00
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Antibody TJ5-5 heavy chain


Mass: 13487.161 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#2: Antibody TJ5-5 light chain


Mass: 11114.028 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#3: Protein Hemagglutinin /


Mass: 55677.242 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Influenza A virus / Gene: HA / Production host: Homo sapiens (human) / References: UniProt: M1ND93

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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
1H3 COBRA HA protein in complex with human antibody TJ5-5COMPLEXall0MULTIPLE SOURCES
2H3 COBRA hemagglutinin proteinCOMPLEX#31RECOMBINANT
3Human antibody TJ5-5COMPLEX#1-#21RECOMBINANT
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
21Homo sapiens (human)9606
32unidentified influenza virus11309
43Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
21Homo sapiens (human)9606
32Homo sapiens (human)9606
43Homo sapiens (human)9606
Details of virus
IDEntity assembly-IDIsolateType
11STRAINVIRION
22
33
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

MicroscopyModel: TFS GLACIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2000 nm / Nominal defocus min: 900 nm
Image recordingElectron dose: 57.22 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: 3.41 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 101267 / Symmetry type: POINT

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