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- PDB-8u1c: A mechanistic understanding of protective influenza B neuraminida... -

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ID or keywords:

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Basic information

Entry
Database: PDB / ID: 8u1c
TitleA mechanistic understanding of protective influenza B neuraminidase mAbs at the airway interface
Components
  • Neuraminidase
  • mAb-400 heavy chain
  • mAb-400 light chain
KeywordsHYDROLASE / Neuraminidase Sialidase
Function / homology
Function and homology information


exo-alpha-sialidase / exo-alpha-sialidase activity / carbohydrate metabolic process / host cell plasma membrane / virion membrane / metal ion binding / membrane
Similarity search - Function
Glycoside hydrolase, family 34 / Neuraminidase / Sialidase superfamily
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
Influenza B virus
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.89 Å
AuthorsFerguson, J.A. / Oeverdieck, S. / Ward, A.B.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)75N93019C00051 United States
CitationJournal: Immunity / Year: 2024
Title: Isolation of human antibodies against influenza B neuraminidase and mechanisms of protection at the airway interface.
Authors: Rachael M Wolters / James A Ferguson / Ivette A Nuñez / Elaine E Chen / Ty Sornberger / Luke Myers / Svearike Oeverdieck / Sai Sundar Rajan Raghavan / Chandrahaas Kona / Laura S Handal / ...Authors: Rachael M Wolters / James A Ferguson / Ivette A Nuñez / Elaine E Chen / Ty Sornberger / Luke Myers / Svearike Oeverdieck / Sai Sundar Rajan Raghavan / Chandrahaas Kona / Laura S Handal / Trevor E Esilu / Edgar Davidson / Benjamin J Doranz / Taylor B Engdahl / Nurgun Kose / Lauren E Williamson / C Buddy Creech / Katherine N Gibson-Corley / Andrew B Ward / James E Crowe /
Abstract: Influenza B viruses (IBVs) comprise a substantial portion of the circulating seasonal human influenza viruses. Here, we describe the isolation of human monoclonal antibodies (mAbs) that recognized ...Influenza B viruses (IBVs) comprise a substantial portion of the circulating seasonal human influenza viruses. Here, we describe the isolation of human monoclonal antibodies (mAbs) that recognized the IBV neuraminidase (NA) glycoprotein from an individual following seasonal vaccination. Competition-binding experiments suggested the antibodies recognized two major antigenic sites. One group, which included mAb FluB-393, broadly inhibited IBV NA sialidase activity, protected prophylactically in vivo, and bound to the lateral corner of NA. The second group contained an active site mAb, FluB-400, that broadly inhibited IBV NA sialidase activity and virus replication in vitro in primary human respiratory epithelial cell cultures and protected against IBV in vivo when administered systemically or intranasally. Overall, the findings described here shape our mechanistic understanding of the human immune response to the IBV NA glycoprotein through the demonstration of two mAb delivery routes for protection against IBV and the identification of potential IBV therapeutic candidates.
History
DepositionAug 31, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 27, 2024Provider: repository / Type: Initial release
Revision 1.1Oct 23, 2024Group: Data collection / Structure summary
Category: em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification
Revision 1.2Apr 9, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
H: mAb-400 heavy chain
L: mAb-400 light chain
A: Neuraminidase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)77,4974
Polymers77,0723
Non-polymers4241
Water00
1
H: mAb-400 heavy chain
L: mAb-400 light chain
A: Neuraminidase
hetero molecules

H: mAb-400 heavy chain
L: mAb-400 light chain
A: Neuraminidase
hetero molecules

H: mAb-400 heavy chain
L: mAb-400 light chain
A: Neuraminidase
hetero molecules

H: mAb-400 heavy chain
L: mAb-400 light chain
A: Neuraminidase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)309,98716
Polymers308,28912
Non-polymers1,6984
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
point symmetry operation3
2


  • Idetical with deposited unit
  • point asymmetric unit
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3


  • Idetical with deposited unit in distinct coordinate
  • point asymmetric unit, std point frame
TypeNameSymmetry operationNumber
transform to point frame1
SymmetryPoint symmetry: (Schoenflies symbol: C4 (4 fold cyclic))

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Components

#1: Antibody mAb-400 heavy chain


Mass: 14438.196 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): ExpiCHO / Production host: Cricetulus griseus (Chinese hamster)
#2: Antibody mAb-400 light chain


Mass: 11529.794 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): ExpiCHO / Production host: Cricetulus griseus (Chinese hamster)
#3: Protein Neuraminidase


Mass: 51104.258 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Influenza B virus (B/Iowa/06/2017) / Gene: NA / Cell line (production host): D2 / Production host: Drosophila melanogaster (fruit fly) / References: UniProt: A0A1S7DL21
#4: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}LINUCSPDB-CARE
Has ligand of interestY
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: Complex of human donor mAb-fv domain bound to influenza B neuraminidase
Type: COMPLEX / Entity ID: #1-#3 / Source: MULTIPLE SOURCES
Molecular weightUnits: MEGADALTONS / Experimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
21Homo sapiens (human)9606
31Influenza B virus (B/Iowa/06/2017)1968240
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-IDCellPlasmid
21Drosophila melanogaster (fruit fly)7227D2pCoBlast
31Cricetulus griseus (Chinese hamster)10029ExpiCHO
Buffer solutionpH: 7.4 / Details: TBS
SpecimenConc.: 0.4 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK III / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 298 K

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Electron microscopy imaging

Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company
MicroscopyModel: FEI TALOS ARCTICA
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 190000 X / Calibrated magnification: 190000 X / Nominal defocus max: 700 nm / Nominal defocus min: 700 nm / Calibrated defocus min: 1500 nm / Calibrated defocus max: 1500 nm / Cs: 2.7 mm / C2 aperture diameter: 100 µm
Specimen holderCryogen: NITROGEN / Specimen holder model: OTHER
Image recordingElectron dose: 49.87 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 5958
Image scansWidth: 4048 / Height: 4048

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Processing

EM software
IDNameCategoryDetails
1cryoSPARCparticle selectionTemplate Picker
2EPUimage acquisition
4cryoSPARCCTF correctionPatchCTF
7Rosettamodel fitting
8PHENIXmodel fitting
10cryoSPARCinitial Euler assignment
11cryoSPARCfinal Euler assignment
13cryoSPARC3D reconstruction
14Cootmodel refinement
CTF correctionType: NONE
Particle selectionNum. of particles selected: 1096437
SymmetryPoint symmetry: C4 (4 fold cyclic)
3D reconstructionResolution: 2.89 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 220989 / Symmetry type: POINT
Atomic model building
ID 3D fitting-IDChain-IDSource nameTypeDetails
11ARoseTTAFoldin silico model
21HLOtherin silico modelhttps://opig.stats.ox.ac.uk/webapps/sabdab-sabpred/sabpred/abodybuilder2_results/20230713_0236990/
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 22.06 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.02314717
ELECTRON MICROSCOPYf_angle_d1.84456385
ELECTRON MICROSCOPYf_chiral_restr0.1084677
ELECTRON MICROSCOPYf_plane_restr0.0097813
ELECTRON MICROSCOPYf_dihedral_angle_d10.1011710

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