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- PDB-8g3n: N2 neuraminidase of A/Tanzania/205/2010 H3N2 in complex with 4 FN... -

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Basic information

Entry
Database: PDB / ID: 8g3n
TitleN2 neuraminidase of A/Tanzania/205/2010 H3N2 in complex with 4 FNI9 Fab molecules
Components
  • FNI9 Fab heavy chain
  • FNI9 Fab light chain
  • Neuraminidase
KeywordsVIRAL PROTEIN/IMMUNE SYSTEM / viral glycoprotein / antibody / Fab / influenza / 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: 2.9 Å
AuthorsDang, H. / 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
G: Neuraminidase
E: FNI9 Fab heavy chain
F: FNI9 Fab light chain
J: Neuraminidase
A: FNI9 Fab heavy chain
D: FNI9 Fab light chain
K: Neuraminidase
B: FNI9 Fab heavy chain
H: FNI9 Fab light chain
L: Neuraminidase
C: FNI9 Fab heavy chain
I: FNI9 Fab light chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)425,74740
Polymers410,95312
Non-polymers14,79428
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11G
21J
12G
22K
13G
23L
14E
24A
15E
25B
16E
26C
17F
27D
18F
28H
19F
29I
110J
210K
111J
211L
112A
212B
113A
213C
114D
214H
115D
215I
116K
216L
117B
217C
118H
218I

NCS domain segments:

Component-ID: 0 / Refine code: 0

Dom-IDEns-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11ALAALAILEILEGA82 - 469105 - 492
21ALAALAILEILEJD82 - 469105 - 492
12ALAALAILEILEGA82 - 469105 - 492
22ALAALAILEILEKG82 - 469105 - 492
13ALAALAILEILEGA82 - 469105 - 492
23ALAALAILEILELJ82 - 469105 - 492
14GLNGLNSERSEREB1 - 1301 - 130
24GLNGLNSERSERAE1 - 1301 - 130
15GLNGLNSERSEREB1 - 1301 - 130
25GLNGLNSERSERBH1 - 1301 - 130
16GLNGLNSERSEREB1 - 1301 - 130
26GLNGLNSERSERCK1 - 1301 - 130
17GLUGLUTHRTHRFC1 - 1101 - 110
27GLUGLUTHRTHRDF1 - 1101 - 110
18GLUGLUTHRTHRFC1 - 1101 - 110
28GLUGLUTHRTHRHI1 - 1101 - 110
19GLUGLUTHRTHRFC1 - 1101 - 110
29GLUGLUTHRTHRIL1 - 1101 - 110
110ALAALAILEILEJD82 - 469105 - 492
210ALAALAILEILEKG82 - 469105 - 492
111ALAALAILEILEJD82 - 469105 - 492
211ALAALAILEILELJ82 - 469105 - 492
112GLNGLNSERSERAE1 - 1301 - 130
212GLNGLNSERSERBH1 - 1301 - 130
113GLNGLNSERSERAE1 - 1301 - 130
213GLNGLNSERSERCK1 - 1301 - 130
114GLUGLUTHRTHRDF1 - 1101 - 110
214GLUGLUTHRTHRHI1 - 1101 - 110
115GLUGLUTHRTHRDF1 - 1101 - 110
215GLUGLUTHRTHRIL1 - 1101 - 110
116ALAALAILEILEKG82 - 469105 - 492
216ALAALAILEILELJ82 - 469105 - 492
117GLNGLNSERSERBH1 - 1301 - 130
217GLNGLNSERSERCK1 - 1301 - 130
118GLUGLUTHRTHRHI1 - 1101 - 110
218GLUGLUTHRTHRIL1 - 1101 - 110

NCS ensembles :
ID
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18

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Components

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Antibody , 2 types, 8 molecules EABCFDHI

#2: Antibody
FNI9 Fab heavy chain


Mass: 24418.053 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Cricetulus griseus (Chinese hamster)
#3: Antibody
FNI9 Fab light chain


Mass: 23565.068 Da / Num. of mol.: 4
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 GJKL

#1: Protein
Neuraminidase /


Mass: 54755.047 Da / Num. of mol.: 4
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: V9SU56
#8: 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 , 4 types, 23 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.: 13
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
beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta- ...beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 586.542 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/2,3,2/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5]/1-1-2/a4-b1_b4-c1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{}}}LINUCSPDB-CARE
#6: 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
#7: 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.: 2
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: 4 FNI9 Fabs in complex with tetrameric N2 NA protein from A/Tanzania/2010 strain
Type: COMPLEX / Entity ID: #1-#3 / Source: RECOMBINANT
Molecular weightValue: 0.42 MDa / Experimental value: NO
Source (natural)Organism: Influenza A virus
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 8 / Details: 50 mM Tris-HCl, 150 mM NaCl, 10 mM CaCl2, pH 8.0
Buffer component
IDConc.NameFormulaBuffer-ID
150 mMTrisC4H11NO31
2150 mMSodium ChlorideNaClSodium chloride1
310 mMCalcium ChlorideCaCl21
SpecimenConc.: 0.1 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid type: C-flat-1.2/1.3
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: 2500 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 48 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: C4 (4 fold cyclic)
3D reconstructionResolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 217552 / Symmetry type: POINT
RefinementResolution: 2.9→159.58 Å / Cor.coef. Fo:Fc: 0.926 / SU B: 9.268 / SU ML: 0.17 / ESU R: 0.302
Stereochemistry target values: MAXIMUM LIKELIHOOD WITH PHASES
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflection
Rwork0.29834 --
obs0.29834 248559 100 %
Solvent computationSolvent model: PARAMETERS FOR MASK CACLULATION
Displacement parametersBiso mean: 87.11 Å2
Refinement stepCycle: 1 / Total: 20321
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
ELECTRON MICROSCOPYr_bond_refined_d0.0110.01320876
ELECTRON MICROSCOPYr_bond_other_d00.01418464
ELECTRON MICROSCOPYr_angle_refined_deg1.7841.71328498
ELECTRON MICROSCOPYr_angle_other_deg1.3621.64142782
ELECTRON MICROSCOPYr_dihedral_angle_1_deg8.02452500
ELECTRON MICROSCOPYr_dihedral_angle_2_deg30.07521.9071028
ELECTRON MICROSCOPYr_dihedral_angle_3_deg11.817153144
ELECTRON MICROSCOPYr_dihedral_angle_4_deg14.59315136
ELECTRON MICROSCOPYr_chiral_restr0.0880.22953
ELECTRON MICROSCOPYr_gen_planes_refined0.0090.0223291
ELECTRON MICROSCOPYr_gen_planes_other0.0020.024886
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_it9.4828.52610036
ELECTRON MICROSCOPYr_mcbond_other9.4828.52310035
ELECTRON MICROSCOPYr_mcangle_it14.67612.79212524
ELECTRON MICROSCOPYr_mcangle_other14.67512.79512525
ELECTRON MICROSCOPYr_scbond_it11.3869.87310840
ELECTRON MICROSCOPYr_scbond_other11.3859.87610841
ELECTRON MICROSCOPYr_scangle_it
ELECTRON MICROSCOPYr_scangle_other18.63214.35715975
ELECTRON MICROSCOPYr_long_range_B_refined28.49178374
ELECTRON MICROSCOPYr_long_range_B_other28.49278371
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)
11G240020.02
12J240020.02
21G240060.02
22K240060.02
31G240020.02
32L240020.02
41E76760.03
42A76760.03
51E77140
52B77140
61E77140
62C77140
71F64740.02
72D64740.02
81F64840
82H64840
91F64840
92I64840
101J240180
102K240180
111J240140
112L240140
121A76760.03
122B76760.03
131A76780.03
132C76780.03
141D64740.02
142H64740.02
151D64740.02
152I64740.02
161K240180
162L240180
171B77180
172C77180
181H64860
182I64860
LS refinement shellResolution: 2.9→2.975 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0 0 -
Rwork1.166 18429 -
obs--100 %

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