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- PDB-9dzq: CryoEM structure of the human antibodies PIV3HN-05 and PIV3HN-13 ... -

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Basic information

Entry
Database: PDB / ID: 9dzq
TitleCryoEM structure of the human antibodies PIV3HN-05 and PIV3HN-13 in complex with the parainfluenza virus hemagglutinin-neuraminidase protein
Components
  • Hemagglutinin-neuraminidase
  • Human antibody PIV3HN-05 heavy chain
  • Human antibody PIV3HN-05 light chain
  • Human antibody PIV3HN-13 heavy chain
  • Human antibody PIV3HN-13 light chain
KeywordsVIRAL PROTEIN/IMMUNE SYSTEM / Hemagglutinin-neuraminidase / human monoclonal antibody / 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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.57 Å
AuthorsMousa, J.J. / Miller, R.J.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R56AI181850 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R01AI173416 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
DepositionOct 16, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 4, 2024Provider: repository / Type: Initial release
Revision 1.1Jan 15, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
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 / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Hemagglutinin-neuraminidase
C: Human antibody PIV3HN-05 heavy chain
E: Human antibody PIV3HN-05 light chain
G: Human antibody PIV3HN-13 heavy chain
I: Human antibody PIV3HN-13 light chain
B: Hemagglutinin-neuraminidase
D: Human antibody PIV3HN-05 heavy chain
F: Human antibody PIV3HN-05 light chain
H: Human antibody PIV3HN-13 heavy chain
J: Human antibody PIV3HN-13 light chain


Theoretical massNumber of molelcules
Total (without water)293,34210
Polymers293,34210
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#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
#2: Antibody Human antibody PIV3HN-05 heavy chain


Mass: 24696.654 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 Human antibody PIV3HN-05 light chain


Mass: 22877.150 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#4: Antibody Human antibody PIV3HN-13 heavy chain


Mass: 23686.352 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#5: Antibody Human antibody PIV3HN-13 light chain


Mass: 23785.422 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
Has protein modificationY

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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: Complex of the PIV3 HN protein with two human antibodies
Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Molecular weightValue: 0.2 MDa / Experimental value: YES
Source (natural)Organism: Human respirovirus 3
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5 / Details: 20 mM Tris, pH 7.5 120 mM NaCl
SpecimenConc.: 1 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES / Details: Monodisperse
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen 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 FIELD / Nominal defocus max: 2600 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 52.8 e/Å2 / Film or detector model: GATAN K2 IS (4k x 4k)

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Processing

EM softwareName: PHENIX / Version: 1.21.2_5419 / Category: model refinement
CTF correctionType: NONE
3D reconstructionResolution: 3.57 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 139192 / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT
RefinementCross valid method: NONE

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