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- PDB-9b2w: PIV3 HN with Fab 13 -

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Basic information

Entry
Database: PDB / ID: 9b2w
TitlePIV3 HN with Fab 13
Components
  • Fab 13 Heavy Chain
  • Fab 13 Light Chain
  • Hemagglutinin-neuraminidase
KeywordsVIRAL PROTEIN/Immune System / HN / hemagglutinin neuraminidase / complex / antibody complex / VIRAL PROTEIN / VIRAL PROTEIN-Immune System complex
Function / homology
Function and homology information


exo-alpha-sialidase activity / host cell surface receptor binding / symbiont entry into host cell / viral envelope / virion attachment to host cell / host cell plasma membrane / virion membrane / membrane
Similarity search - Function
Haemagglutinin-neuraminidase / Haemagglutinin/haemagglutinin-neuraminidase, paramyxovirus / Haemagglutinin-neuraminidase / Sialidase superfamily
Similarity search - Domain/homology
Hemagglutinin-neuraminidase
Similarity search - Component
Biological speciesHuman respirovirus 3
Homo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.51 Å
AuthorsDurie, I.A. / Mousa, J.J.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)5R01AI143865 United States
CitationJournal: Nat Commun / Year: 2024
Title: The structural basis of protective and nonprotective human monoclonal antibodies targeting the parainfluenza virus type 3 hemagglutinin-neuraminidase.
Authors: Rose J Miller / Ian A Durie / Aaron D Gingerich / Mohamed A Elbehairy / Abigail G Branch / Riley G Davis / Nada Abbadi / Melinda A Brindley / Jarrod J Mousa /
Abstract: Parainfluenza virus 3 (PIV3) infection poses a substantial risk to vulnerable groups including infants, the elderly, and immunocompromised individuals, and lacks effective treatments or vaccines. ...Parainfluenza virus 3 (PIV3) infection poses a substantial risk to vulnerable groups including infants, the elderly, and immunocompromised individuals, and lacks effective treatments or vaccines. This study focuses on targeting the hemagglutinin-neuraminidase (HN) protein, a structural glycoprotein of PIV3 critical for viral infection and egress. With the objective of targeting these activities of HN, we identified eight neutralizing human monoclonal antibodies (mAbs) with potent effects on viral neutralization, cell-cell fusion inhibition, and complement deposition. Three epitopes on PIV3 HN were delineated and one epitope, Site 2, elicits a mAb with cross-neutralizing ability against PIV1 and PIV3. Cryo-EM revealed the cross-neutralizing mAb utilizes a long CDR3 loop to bind inside the pocket of the sialic acid binding site. Additionally, we resolved the structure of a non-protective mAb binding to Site 1 near the HN:F-interaction site. The potent Site 2-directed mAb demonstrated clinical efficacy in hamsters, reducing viral replication prophylactically and therapeutically. These findings advance our understanding of PIV3 immunity and underscore the significance of targeting HN for clinical therapeutic development against PIV3.
History
DepositionMar 17, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 4, 2024Provider: repository / Type: Initial release
Revision 1.1Jan 15, 2025Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
D: Hemagglutinin-neuraminidase
A: Hemagglutinin-neuraminidase
B: Fab 13 Heavy Chain
C: Fab 13 Light Chain
E: Fab 13 Heavy Chain
F: Fab 13 Light Chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)201,49416
Polymers197,9886
Non-polymers3,50610
Water23413
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area19200 Å2
ΔGint-93 kcal/mol
Surface area68290 Å2
MethodPISA
Unit cell
Length a, b, c (Å)81.273, 129.353, 89.454
Angle α, β, γ (deg.)90.00, 93.57, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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Protein , 1 types, 2 molecules DA

#1: Protein Hemagglutinin-neuraminidase


Mass: 51625.516 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human respirovirus 3 / Gene: HN / Production host: Homo sapiens (human) / References: UniProt: Q81080

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Antibody , 2 types, 4 molecules BECF

#2: Antibody Fab 13 Heavy Chain


Mass: 23468.115 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#3: Antibody Fab 13 Light Chain


Mass: 23900.510 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)

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Sugars , 5 types, 6 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.: 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
#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.: 2
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 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.: 1
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
#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.: 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
#9: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Non-polymers , 2 types, 17 molecules

#8: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#10: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 13 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestN
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.35 Å3/Da / Density % sol: 47.58 %
Crystal growTemperature: 300 K / Method: vapor diffusion, sitting drop
Details: 0.1M Ammonium sulfate, 0.1M MES pH 6.5, 15% (w/v) PEG 4000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 14-ID-B / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Feb 11, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.51→50 Å / Num. obs: 61212 / % possible obs: 96.95 % / Redundancy: 1.6 % / CC1/2: 0.985 / CC star: 0.996 / Net I/σ(I): 17.8
Reflection shellResolution: 2.51→2.6 Å / Num. unique obs: 5863 / CC1/2: 0.897 / Rpim(I) all: 0.897 / Rrim(I) all: 0.481

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Processing

Software
NameVersionClassification
PHENIX(1.20.1_4487: ???)refinement
HKL-2000data scaling
HKL-2000data reduction
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.51→34.76 Å / SU ML: 0.35 / Cross valid method: NONE / σ(F): 1.36 / Phase error: 28.12 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2644 3099 5.06 %
Rwork0.2192 --
obs0.2214 61212 96.8 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.51→34.76 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms13342 0 227 13 13582
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00413886
X-RAY DIFFRACTIONf_angle_d0.69218909
X-RAY DIFFRACTIONf_dihedral_angle_d5.9011990
X-RAY DIFFRACTIONf_chiral_restr0.0462168
X-RAY DIFFRACTIONf_plane_restr0.0082406
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.51-2.550.37281170.30432364X-RAY DIFFRACTION85
2.55-2.590.30981420.29432554X-RAY DIFFRACTION95
2.59-2.630.33371440.26872621X-RAY DIFFRACTION96
2.63-2.680.32631340.28552633X-RAY DIFFRACTION97
2.68-2.730.31891290.28172616X-RAY DIFFRACTION96
2.73-2.790.31521440.27412626X-RAY DIFFRACTION97
2.79-2.850.34691470.27242639X-RAY DIFFRACTION97
2.85-2.920.32591460.27552662X-RAY DIFFRACTION97
2.92-2.990.34771690.28072605X-RAY DIFFRACTION98
2.99-3.070.33881390.28592692X-RAY DIFFRACTION98
3.07-3.160.31161570.2692536X-RAY DIFFRACTION94
3.16-3.260.33521410.2522691X-RAY DIFFRACTION98
3.26-3.380.3161450.25142654X-RAY DIFFRACTION99
3.38-3.510.25721390.23122711X-RAY DIFFRACTION99
3.51-3.670.27721570.22542698X-RAY DIFFRACTION99
3.67-3.870.2591340.21322722X-RAY DIFFRACTION99
3.87-4.110.23241640.19852667X-RAY DIFFRACTION99
4.11-4.420.22431750.1712659X-RAY DIFFRACTION99
4.42-4.870.17831090.15552611X-RAY DIFFRACTION94
4.87-5.570.18361170.16912752X-RAY DIFFRACTION99
5.57-7.010.21821230.19672747X-RAY DIFFRACTION99
7.01-34.760.20331270.16892653X-RAY DIFFRACTION94

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