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- PDB-8g3m: N2 neuraminidase of A/Tanzania/205/2010 H3N2 in complex with 3 FN... -

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Basic information

Entry
Database: PDB / ID: 8g3m
TitleN2 neuraminidase of A/Tanzania/205/2010 H3N2 in complex with 3 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 speciesInfluenza A virus
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 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
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
L: Neuraminidase
C: FNI9 Fab heavy chain
I: FNI9 Fab light chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)380,42639
Polymers362,97010
Non-polymers17,45629
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
25C
16F
26D
17F
27I
18J
28K
19J
29L
110A
210C
111D
211I
112K
212L

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
23ALAALAILEILELH82 - 469105 - 492
14GLNGLNSERSEREB1 - 1301 - 130
24GLNGLNSERSERAE1 - 1301 - 130
15GLNGLNSERSEREB1 - 1301 - 130
25GLNGLNSERSERCI1 - 1301 - 130
16GLUGLUTHRTHRFC1 - 1101 - 110
26GLUGLUTHRTHRDF1 - 1101 - 110
17GLUGLUTHRTHRFC1 - 1101 - 110
27GLUGLUTHRTHRIJ1 - 1101 - 110
18ALAALAILEILEJD82 - 469105 - 492
28ALAALAILEILEKG82 - 469105 - 492
19ALAALAILEILEJD82 - 469105 - 492
29ALAALAILEILELH82 - 469105 - 492
110GLNGLNSERSERAE1 - 1301 - 130
210GLNGLNSERSERCI1 - 1301 - 130
111GLUGLUTHRTHRDF1 - 1101 - 110
211GLUGLUTHRTHRIJ1 - 1101 - 110
112ALAALAILEILEKG82 - 469105 - 492
212ALAALAILEILELH82 - 469105 - 492

NCS ensembles :
ID
1
2
3
4
5
6
7
8
9
10
11
12

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Components

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Antibody , 2 types, 6 molecules EACFDI

#2: Antibody FNI9 Fab heavy chain


Mass: 24418.053 Da / Num. of mol.: 3
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.: 3
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
#9: 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 , 5 types, 24 molecules

#4: 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
#5: Polysaccharide
alpha-D-mannopyranose-(1-6)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1- ...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: 748.682 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-6DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/3,4,3/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3/a4-b1_b4-c1_c6-d1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(6+1)][a-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
beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1- ...beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 732.682 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpb1-4DGlcpNAcb1-4[LFucpa1-6]DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/3,4,3/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1221m-1a_1-5]/1-1-2-3/a4-b1_a6-d1_b4-c1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{}}[(6+1)][a-L-Fucp]{}}LINUCSPDB-CARE
#8: 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.: 8
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

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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/Tanzania/205/2010 H3N2 in complex with 3 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)
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.: 0.2 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: 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: C1 (asymmetric)
3D reconstructionResolution: 3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 217552 / Symmetry type: POINT
RefinementResolution: 3→157.39 Å / Cor.coef. Fo:Fc: 0.9 / SU B: 15.14 / SU ML: 0.268 / ESU R: 0.387
Stereochemistry target values: MAXIMUM LIKELIHOOD WITH PHASES
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflection
Rwork0.35864 --
obs0.35864 218960 100 %
Solvent computationSolvent model: PARAMETERS FOR MASK CACLULATION
Displacement parametersBiso mean: 97.014 Å2
Refinement stepCycle: 1 / Total: 18667
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
ELECTRON MICROSCOPYr_bond_refined_d0.010.01319193
ELECTRON MICROSCOPYr_bond_other_d00.01416915
ELECTRON MICROSCOPYr_angle_refined_deg1.8111.73526237
ELECTRON MICROSCOPYr_angle_other_deg1.3491.65939279
ELECTRON MICROSCOPYr_dihedral_angle_1_deg5.76352262
ELECTRON MICROSCOPYr_dihedral_angle_2_deg30.3521.942932
ELECTRON MICROSCOPYr_dihedral_angle_3_deg11.766152861
ELECTRON MICROSCOPYr_dihedral_angle_4_deg14.86215123
ELECTRON MICROSCOPYr_chiral_restr0.0840.22784
ELECTRON MICROSCOPYr_gen_planes_refined0.0090.0221124
ELECTRON MICROSCOPYr_gen_planes_other0.0020.024412
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_it9.7959.3359078
ELECTRON MICROSCOPYr_mcbond_other9.7959.3329077
ELECTRON MICROSCOPYr_mcangle_it15.53113.99311330
ELECTRON MICROSCOPYr_mcangle_other15.5313.99611331
ELECTRON MICROSCOPYr_scbond_it11.4211.32610115
ELECTRON MICROSCOPYr_scbond_other11.41911.32810116
ELECTRON MICROSCOPYr_scangle_it
ELECTRON MICROSCOPYr_scangle_other19.20716.54714908
ELECTRON MICROSCOPYr_long_range_B_refined31.00472363
ELECTRON MICROSCOPYr_long_range_B_other31.00572360
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)
11G238820.02
12J238820.02
21G235640.07
22K235640.07
31G239340.01
32L239340.01
41E76340.02
42A76340.02
51E76420.02
52C76420.02
61F64000.02
62D64000.02
71F63580.03
72I63580.03
81J235340.07
82K235340.07
91J238660.02
92L238660.02
101A76340.01
102C76340.01
111D63620.02
112I63620.02
121K235900.07
122L235900.07
LS refinement shellResolution: 3→3.078 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0 0 -
Rwork0.961 16285 -
obs--100 %

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