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- PDB-8g3p: N2 neuraminidase of A/Hong_Kong/2671/2019 in complex with 4 FNI9 ... -

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Basic information

Entry
Database: PDB / ID: 8g3p
TitleN2 neuraminidase of A/Hong_Kong/2671/2019 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 / 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 speciesHomo sapiens (human)
Influenza A virus
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.5 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
C: FNI9 Fab heavy chain
I: FNI9 Fab light chain
B: Neuraminidase
F: FNI9 Fab heavy chain
J: FNI9 Fab light chain
A: Neuraminidase
G: FNI9 Fab heavy chain
K: FNI9 Fab light chain
D: Neuraminidase
H: FNI9 Fab heavy chain
L: FNI9 Fab light chain
E: Neuraminidase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)425,07841
Polymers410,21612
Non-polymers14,86229
Water0
1


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

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
11GLNGLNSERSERCA1 - 1301 - 130
21GLNGLNSERSERFD1 - 1301 - 130
12GLNGLNSERSERCA1 - 1301 - 130
22GLNGLNSERSERGG1 - 1301 - 130
13GLNGLNSERSERCA1 - 1301 - 130
23GLNGLNSERSERHJ1 - 1301 - 130
14GLUGLUTHRTHRIB1 - 1101 - 110
24GLUGLUTHRTHRJE1 - 1101 - 110
15GLUGLUTHRTHRIB1 - 1101 - 110
25GLUGLUTHRTHRKH1 - 1101 - 110
16GLUGLUTHRTHRIB1 - 1101 - 110
26GLUGLUTHRTHRLK1 - 1101 - 110
17ALAALATHRTHRBC82 - 469105 - 492
27ALAALATHRTHRAF82 - 469105 - 492
18ALAALATHRTHRBC82 - 469105 - 492
28ALAALATHRTHRDI82 - 469105 - 492
19ALAALATHRTHRBC82 - 469105 - 492
29ALAALATHRTHREL82 - 469105 - 492
110GLNGLNSERSERFD1 - 1301 - 130
210GLNGLNSERSERGG1 - 1301 - 130
111GLNGLNSERSERFD1 - 1301 - 130
211GLNGLNSERSERHJ1 - 1301 - 130
112GLUGLUTHRTHRJE1 - 1101 - 110
212GLUGLUTHRTHRKH1 - 1101 - 110
113GLUGLUTHRTHRJE1 - 1101 - 110
213GLUGLUTHRTHRLK1 - 1101 - 110
114ALAALATHRTHRAF82 - 469105 - 492
214ALAALATHRTHRDI82 - 469105 - 492
115ALAALATHRTHRAF82 - 469105 - 492
215ALAALATHRTHREL82 - 469105 - 492
116GLNGLNSERSERGG1 - 1301 - 130
216GLNGLNSERSERHJ1 - 1301 - 130
117GLUGLUTHRTHRKH1 - 1101 - 110
217GLUGLUTHRTHRLK1 - 1101 - 110
118ALAALATHRTHRDI82 - 469105 - 492
218ALAALATHRTHREL82 - 469105 - 492

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 CFGHIJKL

#1: 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)
#2: 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 BADE

#3: Protein
Neuraminidase /


Mass: 54570.906 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Details: A/Hong_Kong/2671/2019 / Source: (gene. exp.) Influenza A virus / Gene: NA / Production host: Homo sapiens (human) / References: UniProt: A0A411D019
#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, 24 molecules

#4: 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
#5: 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.: 16
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
#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.: 4
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: N2 neuraminidase of A/Hong_Kong/2671/2019 in complex with 4 FNI9 Fab molecules
Type: COMPLEX
Details: Fab fragment generated by proteolytic cleavage of FNI9 IgG1 antibody
Entity ID: #1-#3 / Source: RECOMBINANT
Molecular weightValue: 0.42 kDa/nm / 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
1150 mMsodium chlorideNaClSodium chloride1
250 mMTrisC4H11NO31
310 mMcalcium chlorideCaCl21
SpecimenConc.: 0.2 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
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: 1800 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 52.32 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: 2.5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 162364 / Symmetry type: POINT
RefinementResolution: 2.5→175.96 Å / Cor.coef. Fo:Fc: 0.91 / SU B: 5.655 / SU ML: 0.116 / ESU R: 0.177
Stereochemistry target values: MAXIMUM LIKELIHOOD WITH PHASES
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflection
Rwork0.31169 --
obs0.31169 475363 100 %
Solvent computationSolvent model: PARAMETERS FOR MASK CACLULATION
Displacement parametersBiso mean: 73.544 Å2
Refinement stepCycle: 1 / Total: 20321
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
ELECTRON MICROSCOPYr_bond_refined_d0.010.01320872
ELECTRON MICROSCOPYr_bond_other_d00.01418460
ELECTRON MICROSCOPYr_angle_refined_deg1.6931.71328484
ELECTRON MICROSCOPYr_angle_other_deg1.3911.64242744
ELECTRON MICROSCOPYr_dihedral_angle_1_deg8.37352500
ELECTRON MICROSCOPYr_dihedral_angle_2_deg30.21721.8991032
ELECTRON MICROSCOPYr_dihedral_angle_3_deg11.651153144
ELECTRON MICROSCOPYr_dihedral_angle_4_deg17.16215136
ELECTRON MICROSCOPYr_chiral_restr0.0870.22948
ELECTRON MICROSCOPYr_gen_planes_refined0.0080.0223300
ELECTRON MICROSCOPYr_gen_planes_other0.0020.024912
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_it6.6367.34210036
ELECTRON MICROSCOPYr_mcbond_other6.6357.34110035
ELECTRON MICROSCOPYr_mcangle_it10.36711.03112524
ELECTRON MICROSCOPYr_mcangle_other10.36711.03212525
ELECTRON MICROSCOPYr_scbond_it7.7758.23910836
ELECTRON MICROSCOPYr_scbond_other7.7748.2410837
ELECTRON MICROSCOPYr_scangle_it
ELECTRON MICROSCOPYr_scangle_other12.85712.05315961
ELECTRON MICROSCOPYr_long_range_B_refined19.42584444
ELECTRON MICROSCOPYr_long_range_B_other19.42584445
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)
11C79220
12F79220
21C79200
22G79200
31C79180.01
32H79180.01
41I67540
42J67540
51I67560
52K67560
61I67440.01
62L67440.01
71B264900
72A264900
81B264900.01
82D264900.01
91B265060
92E265060
101F79200
102G79200
111F79180.01
112H79180.01
121J67540
122K67540
131J67380.01
132L67380.01
141A265140.01
142D265140.01
151A264900
152E264900
161G79140.01
162H79140.01
171K67400.01
172L67400.01
181D264900.01
182E264900.01
LS refinement shellResolution: 2.5→2.565 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0 0 -
Rwork1.086 35143 -
obs--100 %

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