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- PDB-8g3r: N2 neuraminidase of A/Tanzania/205/2010 H3N2 with S245N S247T mut... -

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Basic information

Entry
Database: PDB / ID: 8g3r
TitleN2 neuraminidase of A/Tanzania/205/2010 H3N2 with S245N S247T mutations in complex with one FNI17 Fab molecule
Components
  • FNI17 Fab heavy chain
  • FNI17 Fab light chain
  • Neuraminidase
KeywordsVIRAL PROTEIN/IMMUNE SYSTEM / viral glycoprotein / antibody / Fab / influenza / virus / VIRAL PROTEIN-IMMUNE SYSTEM complex
Function / homology
Function and homology information


exo-alpha-(2->3)-sialidase activity / exo-alpha-(2->6)-sialidase activity / exo-alpha-(2->8)-sialidase activity / exo-alpha-sialidase / viral budding from plasma membrane / carbohydrate metabolic process / host cell plasma membrane / virion membrane / membrane / metal ion binding
Similarity search - Function
Sialidase, Influenza viruses A/B / Glycoside hydrolase, family 34 / Neuraminidase / Sialidase superfamily
Similarity search - Domain/homology
Biological speciesInfluenza A virus
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.3 Å
AuthorsDang, H.V. / Snell, G.
Funding support United States, 1items
OrganizationGrant numberCountry
Other private United States
CitationJournal: Nature / Year: 2023
Title: A pan-influenza antibody inhibiting neuraminidase via receptor mimicry.
Authors: Corey Momont / Ha V Dang / Fabrizia Zatta / Kevin Hauser / Caihong Wang / Julia di Iulio / Andrea Minola / Nadine Czudnochowski / Anna De Marco / Kaitlin Branch / David Donermeyer / Siddhant ...Authors: Corey Momont / Ha V Dang / Fabrizia Zatta / Kevin Hauser / Caihong Wang / Julia di Iulio / Andrea Minola / Nadine Czudnochowski / Anna De Marco / Kaitlin Branch / David Donermeyer / Siddhant Vyas / Alex Chen / Elena Ferri / Barbara Guarino / Abigail E Powell / Roberto Spreafico / Samantha S Yim / Dale R Balce / Istvan Bartha / Marcel Meury / Tristan I Croll / David M Belnap / Michael A Schmid / William Timothy Schaiff / Jessica L Miller / Elisabetta Cameroni / Amalio Telenti / Herbert W Virgin / Laura E Rosen / Lisa A Purcell / Antonio Lanzavecchia / Gyorgy Snell / Davide Corti / Matteo Samuele Pizzuto /
Abstract: Rapidly evolving influenza A viruses (IAVs) and influenza B viruses (IBVs) are major causes of recurrent lower respiratory tract infections. Current influenza vaccines elicit antibodies ...Rapidly evolving influenza A viruses (IAVs) and influenza B viruses (IBVs) are major causes of recurrent lower respiratory tract infections. Current influenza vaccines elicit antibodies predominantly to the highly variable head region of haemagglutinin and their effectiveness is limited by viral drift and suboptimal immune responses. Here we describe a neuraminidase-targeting monoclonal antibody, FNI9, that potently inhibits the enzymatic activity of all group 1 and group 2 IAVs, as well as Victoria/2/87-like, Yamagata/16/88-like and ancestral IBVs. FNI9 broadly neutralizes seasonal IAVs and IBVs, including the immune-evading H3N2 strains bearing an N-glycan at position 245, and shows synergistic activity when combined with anti-haemagglutinin stem-directed antibodies. Structural analysis reveals that D107 in the FNI9 heavy chain complementarity-determinant region 3 mimics the interaction of the sialic acid carboxyl group with the three highly conserved arginine residues (R118, R292 and R371) of the neuraminidase catalytic site. FNI9 demonstrates potent prophylactic activity against lethal IAV and IBV infections in mice. The unprecedented breadth and potency of the FNI9 monoclonal antibody supports its development for the prevention of influenza illness by seasonal and pandemic viruses.
History
DepositionFeb 8, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 31, 2023Provider: repository / Type: Initial release
Revision 1.1Jun 14, 2023Group: Database references / Category: citation / citation_author / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Jun 28, 2023Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
E: Neuraminidase
G: Neuraminidase
B: FNI17 Fab light chain
C: FNI17 Fab heavy chain
F: Neuraminidase
H: Neuraminidase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)282,62939
Polymers266,5076
Non-polymers16,12133
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11E
21G
12E
22F
13E
23H
14G
24F
15G
25H
16F
26H

NCS domain segments:

Component-ID: 0 / Beg auth comp-ID: ALA / Beg label comp-ID: ALA / End auth comp-ID: ILE / End label comp-ID: ILE / Refine code: 0 / Auth seq-ID: 82 - 469 / Label seq-ID: 105 - 492

Dom-IDEns-IDAuth asym-IDLabel asym-ID
11EA
21GB
12EA
22FE
13EA
23HF
14GB
24FE
15GB
25HF
16FE
26HF

NCS ensembles :
ID
1
2
3
4
5
6

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Components

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Antibody , 2 types, 2 molecules BC

#2: Antibody FNI17 Fab light chain


Mass: 23479.061 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)
#3: Antibody FNI17 Fab heavy chain


Mass: 24580.527 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)

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Protein / Non-polymers , 2 types, 9 molecules EGFH

#1: Protein
Neuraminidase /


Mass: 54611.969 Da / Num. of mol.: 4 / Mutation: S245N, S247T
Source method: isolated from a genetically manipulated source
Details: A/Tanzania/205/2010 H3N2 / Source: (gene. exp.) Influenza A virus / Gene: NA / Production host: Homo sapiens (human) / References: UniProt: V9SNF2
#7: Chemical
ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: Ca / Feature type: SUBJECT OF INVESTIGATION

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Sugars , 3 types, 28 molecules

#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.: 23
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
#5: Polysaccharide
alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-3)-[alpha-D- ...alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 1397.245 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-2DManpa1-3[DManpa1-3[DManpa1-6]DManpa1-6]DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/3,8,7/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3-3-3-3-3/a4-b1_b4-c1_c3-d1_c6-f1_d2-e1_f3-g1_f6-h1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(3+1)][a-D-Manp]{[(2+1)][a-D-Manp]{}}[(6+1)][a-D-Manp]{[(3+1)][a-D-Manp]{}[(6+1)][a-D-Manp]{}}}}}LINUCSPDB-CARE
#6: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta- ...2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 570.542 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4[LFucpa1-6]DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/2,3,2/[a2122h-1b_1-5_2*NCC/3=O][a1221m-1a_1-5]/1-1-2/a4-b1_a6-c1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}[(6+1)][a-L-Fucp]{}}LINUCSPDB-CARE

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Details

Has ligand of interestY

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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: One FNI17 Fab in complex with tetrameric N2 NA protein from A/Tanzania/2010 strain with S245N S247T mutations
Type: COMPLEX
Details: Fab fragment generated by proteolytic cleavage of FNI17 IgG1 antibody
Entity ID: #1-#3 / Source: RECOMBINANT
Molecular weightValue: 0.42 kDa/nm / Experimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
21Influenza A virus11320
31Influenza A virus11320
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
21Homo sapiens (human)9606
31Homo sapiens (human)9606
Buffer solutionpH: 8 / Details: 50 mM Tris-HCl, 150 mM NaCl, 10 mM CaCl2, pH 8.0
Buffer component
IDConc.NameFormulaBuffer-ID
1150 mMsodium chlorideNaClSodium chloride1
250 mMTrisC4H11NO31
310 mMcalcium chlorideCaCl21
SpecimenConc.: 0.25 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid type: UltrAuFoil R1.2/1.3
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 FIELDBright-field microscopy / Nominal defocus max: 1500 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 53.81 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

SoftwareName: REFMAC / Version: 5.8.0267 / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 2.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 528681 / Symmetry type: POINT
RefinementResolution: 2.3→180.94 Å / Cor.coef. Fo:Fc: 0.84 / SU B: 5.468 / SU ML: 0.12 / ESU R: 0.178
Stereochemistry target values: MAXIMUM LIKELIHOOD WITH PHASES
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflection
Rwork0.3573 --
obs0.3573 416378 100 %
Solvent computationSolvent model: PARAMETERS FOR MASK CACLULATION
Displacement parametersBiso mean: 82.646 Å2
Refinement stepCycle: 1 / Total: 16432
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
ELECTRON MICROSCOPYr_bond_refined_d0.010.01316896
ELECTRON MICROSCOPYr_bond_other_d0.0320.01415013
ELECTRON MICROSCOPYr_angle_refined_deg1.7011.73723101
ELECTRON MICROSCOPYr_angle_other_deg1.3911.66434902
ELECTRON MICROSCOPYr_dihedral_angle_1_deg8.83451989
ELECTRON MICROSCOPYr_dihedral_angle_2_deg32.23522.261796
ELECTRON MICROSCOPYr_dihedral_angle_3_deg12.199152554
ELECTRON MICROSCOPYr_dihedral_angle_4_deg18.771599
ELECTRON MICROSCOPYr_chiral_restr0.0880.22439
ELECTRON MICROSCOPYr_gen_planes_refined0.0090.0218553
ELECTRON MICROSCOPYr_gen_planes_other0.0020.023781
ELECTRON MICROSCOPYr_nbd_refined
ELECTRON MICROSCOPYr_nbd_other
ELECTRON MICROSCOPYr_nbtor_refined
ELECTRON MICROSCOPYr_nbtor_other
ELECTRON MICROSCOPYr_xyhbond_nbd_refined
ELECTRON MICROSCOPYr_xyhbond_nbd_other
ELECTRON MICROSCOPYr_metal_ion_refined
ELECTRON MICROSCOPYr_metal_ion_other
ELECTRON MICROSCOPYr_symmetry_vdw_refined
ELECTRON MICROSCOPYr_symmetry_vdw_other
ELECTRON MICROSCOPYr_symmetry_hbond_refined
ELECTRON MICROSCOPYr_symmetry_hbond_other
ELECTRON MICROSCOPYr_symmetry_metal_ion_refined
ELECTRON MICROSCOPYr_symmetry_metal_ion_other
ELECTRON MICROSCOPYr_mcbond_it4.3548.5457974
ELECTRON MICROSCOPYr_mcbond_other4.3518.5457973
ELECTRON MICROSCOPYr_mcangle_it6.97712.8319957
ELECTRON MICROSCOPYr_mcangle_other6.97812.8329958
ELECTRON MICROSCOPYr_scbond_it5.3419.088922
ELECTRON MICROSCOPYr_scbond_other5.3419.0818923
ELECTRON MICROSCOPYr_scangle_it
ELECTRON MICROSCOPYr_scangle_other9.00613.4513145
ELECTRON MICROSCOPYr_long_range_B_refined15.34770012
ELECTRON MICROSCOPYr_long_range_B_other15.34770013
ELECTRON MICROSCOPYr_rigid_bond_restr
ELECTRON MICROSCOPYr_sphericity_free
ELECTRON MICROSCOPYr_sphericity_bonded
Refine LS restraints NCS

Refine-ID: ELECTRON MICROSCOPY / Type: interatomic distance / Weight position: 0.05

Ens-IDDom-IDAuth asym-IDNumberRms dev position (Å)
11E257880.08
12G257880.08
21E265740.04
22F265740.04
31E265200.04
32H265200.04
41G257980.08
42F257980.08
51G258840.08
52H258840.08
61F265540.04
62H265540.04
LS refinement shellResolution: 2.3→2.36 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0 0 -
Rwork0.873 30922 -
obs--100 %

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