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- EMDB-47333: CryoEM structure of the human antibodies PIV3HN-05 and PIV3HN-13 ... -

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Basic information

Entry
Database: EMDB / ID: EMD-47333
TitleCryoEM structure of the human antibodies PIV3HN-05 and PIV3HN-13 in complex with the parainfluenza virus hemagglutinin-neuraminidase protein
Map dataUnsharpened map from nonuniform refinement
Sample
  • Complex: Complex of the PIV3 HN protein with two human antibodies
    • Protein or peptide: Hemagglutinin-neuraminidase
    • Protein or peptide: Human antibody PIV3HN-05 heavy chain
    • Protein or peptide: Human antibody PIV3HN-05 light chain
    • Protein or peptide: Human antibody PIV3HN-13 heavy chain
    • Protein or peptide: Human antibody PIV3HN-13 light chain
KeywordsHemagglutinin-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)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.57 Å
AuthorsMousa JJ / Miller RJ
Funding support United States, 2 items
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, 2024-
Header (metadata) releaseDec 4, 2024-
Map releaseDec 4, 2024-
UpdateJan 15, 2025-
Current statusJan 15, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_47333.png

Downloads & links

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Map

FileDownload / File: emd_47333.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationUnsharpened map from nonuniform refinement
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.03 Å/pix.
x 400 pix.
= 412. Å		1.03 Å/pix.
x 400 pix.
= 412. Å		1.03 Å/pix.
x 400 pix.
= 412. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.03 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.117
Minimum - Maximum-0.0017620996 - 2.3009937
Average (Standard dev.)0.00042969378 (±0.014930101)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions400400400
Spacing400400400
CellA=B=C: 412.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: #1

Fileemd_47333_additional_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Unsharpened map from nonuniform refinement

Fileemd_47333_half_map_1.map
AnnotationUnsharpened map from nonuniform refinement
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Unsharpened map from nonuniform refinement

Fileemd_47333_half_map_2.map
AnnotationUnsharpened map from nonuniform refinement
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Complex of the PIV3 HN protein with two human antibodies

EntireName: Complex of the PIV3 HN protein with two human antibodies
Components
  • Complex: Complex of the PIV3 HN protein with two human antibodies
    • Protein or peptide: Hemagglutinin-neuraminidase
    • Protein or peptide: Human antibody PIV3HN-05 heavy chain
    • Protein or peptide: Human antibody PIV3HN-05 light chain
    • Protein or peptide: Human antibody PIV3HN-13 heavy chain
    • Protein or peptide: Human antibody PIV3HN-13 light chain

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Supramolecule #1: Complex of the PIV3 HN protein with two human antibodies

SupramoleculeName: Complex of the PIV3 HN protein with two human antibodies
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Human respirovirus 3
Molecular weightTheoretical: 200 KDa

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Macromolecule #1: Hemagglutinin-neuraminidase

MacromoleculeName: Hemagglutinin-neuraminidase / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Human respirovirus 3
Molecular weightTheoretical: 51.625516 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: HHHHHHSLVP RGSISEITIR NDNQEVLPQR ITHDVGIKPL NPDDFWRCTS GLPSLMKTPK IRLMPGPGLL AMPTTVDGCV RTPSLVIND LIYAYTSNLI TRGCQDIGKS YQVLQIGIIT VNSDLVPDLN PRISHTFNIN DNRKSCSLAL LNTDVYQLCS T PKVDERSD ...String:
HHHHHHSLVP RGSISEITIR NDNQEVLPQR ITHDVGIKPL NPDDFWRCTS GLPSLMKTPK IRLMPGPGLL AMPTTVDGCV RTPSLVIND LIYAYTSNLI TRGCQDIGKS YQVLQIGIIT VNSDLVPDLN PRISHTFNIN DNRKSCSLAL LNTDVYQLCS T PKVDERSD YASSGIEDIV LDIVNYDGSI STTRFKNNNI SFDQPYAALY PSVGPGIYYK GKIIFLGYGG LEHPINENVI CN TTGCPGK TQRDCNQASH SPWFSDRRMV NSIIVADKGL NSIPKLKVWT ISMRQNYWGS EGRLLLLGNK IYIYTRSTSW HSK LQLGII DITDYSDIRI KWTWHNVLSR PGNNECPWGH SCPDGCITGV YTDAYPLNPT GSIVSSVILD SQKSRVNPVI TYST ATERV NELAILNRTL SAGYTTTSCI THYNKGYCFH IVEINHKSLN TFQPMLFKTE IPKSCS

UniProtKB: Hemagglutinin-neuraminidase

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Macromolecule #2: Human antibody PIV3HN-05 heavy chain

MacromoleculeName: Human antibody PIV3HN-05 heavy chain / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 24.696654 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: EVQLVESGGG VVQPGGSLRL SCVASGLSLS PNWMHWVRQA PGKGLVWVSR ISDNGDTTNY AGSVMGRFTI SRDNAKNTLY LQMNNLRAD DTAVYFCVRE SAVISSPSWG LYDTAYHFDP WGQGTLVTVS SASTKGPSVF PLAPSSKSTS GGTAALGCLV K DYFPEPVT ...String:
EVQLVESGGG VVQPGGSLRL SCVASGLSLS PNWMHWVRQA PGKGLVWVSR ISDNGDTTNY AGSVMGRFTI SRDNAKNTLY LQMNNLRAD DTAVYFCVRE SAVISSPSWG LYDTAYHFDP WGQGTLVTVS SASTKGPSVF PLAPSSKSTS GGTAALGCLV K DYFPEPVT VSWNSGALTS GVHTFPAVLQ SSGLYSLSSV VTVPSSSLGT QTYICNVNHK PSNTKVDKRV EPKSC

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Macromolecule #3: Human antibody PIV3HN-05 light chain

MacromoleculeName: Human antibody PIV3HN-05 light chain / type: protein_or_peptide / ID: 3 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 22.87715 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: QSVLTQPPSA SGTPGQGVTI SCSGSNSNIG TNAVDWYQQF PGTAPRLLIF NDNQRPSGVP DRFSGSRSGT SASLAISGLQ SEDEAVYYC ATWDDSLNGP VVFGGGTKLT VLRQPKAAPS VTLFPPSSEE LQANKATLVC LISDFYPGAV TVAWKADSSP V KAGVETTT ...String:
QSVLTQPPSA SGTPGQGVTI SCSGSNSNIG TNAVDWYQQF PGTAPRLLIF NDNQRPSGVP DRFSGSRSGT SASLAISGLQ SEDEAVYYC ATWDDSLNGP VVFGGGTKLT VLRQPKAAPS VTLFPPSSEE LQANKATLVC LISDFYPGAV TVAWKADSSP V KAGVETTT PSKQSNNKYA ASSYLSLTPE QWKSHRSYSC QVTHEGSTVE KTVAPTECS

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Macromolecule #4: Human antibody PIV3HN-13 heavy chain

MacromoleculeName: Human antibody PIV3HN-13 heavy chain / type: protein_or_peptide / ID: 4 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.686352 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: EVQLLESGGA LVQPGGSLRV SCAASGFSFS SYAMSWLRQT PGKGLEWVSA IGGSGHSTYY ADSVQGRFTV SRDNSKDTLY LQMNSLRAE DTAVYYCAKF FRSDGVFHFD YWGPGNPGSP SPASTKGPSV FPLAPSSKST SGGTAALGCL VKDYFPEPVT V SWNSGALT ...String:
EVQLLESGGA LVQPGGSLRV SCAASGFSFS SYAMSWLRQT PGKGLEWVSA IGGSGHSTYY ADSVQGRFTV SRDNSKDTLY LQMNSLRAE DTAVYYCAKF FRSDGVFHFD YWGPGNPGSP SPASTKGPSV FPLAPSSKST SGGTAALGCL VKDYFPEPVT V SWNSGALT SGVHTFPAVL QSSGLYSLSS VVTVPSSSLG TQTYICNVNH KPSNTKVDKR VEPKSC

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Macromolecule #5: Human antibody PIV3HN-13 light chain

MacromoleculeName: Human antibody PIV3HN-13 light chain / type: protein_or_peptide / ID: 5 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.785422 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: DIVMTQSPLS LPVTPGEPAS ISCRSSQSLR HSDGNNYLDW YLQKPGQSPQ LLIYLGSNRA SGVPDRFSGS GSGSDFTLKI SRVEAEDVG VYYCMQALQT PTFGQGTKVE IKRTVAAPSV FIFPPSDEQL KSGTASVVCL LNNFYPREAK VQWKVDNALQ S GNSQESVT ...String:
DIVMTQSPLS LPVTPGEPAS ISCRSSQSLR HSDGNNYLDW YLQKPGQSPQ LLIYLGSNRA SGVPDRFSGS GSGSDFTLKI SRVEAEDVG VYYCMQALQT PTFGQGTKVE IKRTVAAPSV FIFPPSDEQL KSGTASVVCL LNNFYPREAK VQWKVDNALQ S GNSQESVT EQDSKDSTYS LSSTLTLSKA DYEKHKVYAC EVTHQGLSSP VTKSFNRGEC

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration1 mg/mL
BufferpH: 7.5 / Details: 20 mM Tris, pH 7.5 120 mM NaCl
VitrificationCryogen name: ETHANE / Instrument: FEI VITROBOT MARK IV
DetailsMonodisperse

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K2 IS (4k x 4k) / Average electron dose: 52.8 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.6 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: INSILICO MODEL / In silico model: alphafold3
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.57 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 139192
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementProtocol: RIGID BODY FIT
Output model

PDB-9dzq:
CryoEM structure of the human antibodies PIV3HN-05 and PIV3HN-13 in complex with the parainfluenza virus hemagglutinin-neuraminidase protein

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