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- EMDB-19525: Nipah virus (NiV) fusion protein in complex with neutralizing Fab92 -

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Basic information

Entry
Database: EMDB / ID: EMD-19525
TitleNipah virus (NiV) fusion protein in complex with neutralizing Fab92
Map dataNipah virus (NiV) fusion protein in complex with neutralizing Fab92
Sample
  • Complex: Nipah virus fusion (F) glycoprotein in complex with Fab92
    • Protein or peptide: Fusion glycoprotein F0
    • Protein or peptide: Fab92 heavy chain
    • Protein or peptide: Fab92 light chain
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
KeywordsNipah / antibody / neutralization / fusion protein / glycoprotein / VIRAL PROTEIN
Function / homology
Function and homology information


membrane fusion involved in viral entry into host cell / symbiont entry into host cell / fusion of virus membrane with host plasma membrane / viral envelope / host cell plasma membrane / virion membrane / membrane
Similarity search - Function
Precursor fusion glycoprotein F0, Paramyxoviridae / Fusion glycoprotein F0
Similarity search - Domain/homology
Fusion glycoprotein F0
Similarity search - Component
Biological speciesHenipavirus nipahense / Oryctolagus cuniculus (rabbit)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.5 Å
AuthorsAvanzato VA / Stass R / Duyvesteyn HME / Bowden TA
Funding support United Kingdom, 1 items
OrganizationGrant numberCountry
Medical Research Council (MRC, United Kingdom) United Kingdom
CitationJournal: J Virol / Year: 2024
Title: A monoclonal antibody targeting the Nipah virus fusion glycoprotein apex imparts protection from disease.
Authors: Victoria A Avanzato / Trenton Bushmaker / Kasopefoluwa Y Oguntuyo / Claude Kwe Yinda / Helen M E Duyvesteyn / Robert Stass / Kimberly Meade-White / Rebecca Rosenke / Tina Thomas / Neeltje ...Authors: Victoria A Avanzato / Trenton Bushmaker / Kasopefoluwa Y Oguntuyo / Claude Kwe Yinda / Helen M E Duyvesteyn / Robert Stass / Kimberly Meade-White / Rebecca Rosenke / Tina Thomas / Neeltje van Doremalen / Greg Saturday / Katie J Doores / Benhur Lee / Thomas A Bowden / Vincent J Munster /
Abstract: Nipah virus (NiV) is a highly pathogenic paramyxovirus capable of causing severe respiratory and neurologic disease in humans. Currently, there are no licensed vaccines or therapeutics against NiV, ...Nipah virus (NiV) is a highly pathogenic paramyxovirus capable of causing severe respiratory and neurologic disease in humans. Currently, there are no licensed vaccines or therapeutics against NiV, underscoring the urgent need for the development of countermeasures. The NiV surface-displayed glycoproteins, NiV-G and NiV-F, mediate host cell attachment and fusion, respectively, and are heavily targeted by host antibodies. Here, we describe a vaccination-derived neutralizing monoclonal antibody, mAb92, that targets NiV-F. Structural characterization of the Fab region bound to NiV-F (NiV-F-Fab92) by cryo-electron microscopy analysis reveals an epitope in the DIII domain at the membrane distal apex of NiV-F, an established site of vulnerability on the NiV surface. Further, prophylactic treatment of hamsters with mAb92 offered complete protection from NiV disease, demonstrating beneficial activity of mAb92 . This work provides support for targeting NiV-F in the development of vaccines and therapeutics against NiV.IMPORTANCENipah virus (NiV) is a highly lethal henipavirus (HNV) that causes severe respiratory and neurologic disease in humans. Currently, there are no licensed vaccines or therapeutics against NiV, highlighting a need to develop countermeasures. The NiV surface displays the receptor binding protein (NiV-G, or RBP) and the fusion protein (NiV-F), which allow the virus to attach and enter cells. These proteins can be targeted by vaccines and antibodies to prevent disease. This work describes a neutralizing antibody (mAb92) that targets NiV-F. Structural characterization by cryo-electron microscopy analysis reveals where the antibody binds to NiV-F to neutralize the virus. This study also shows that prophylactic treatment of hamsters with mAb92 completely protected against developing NiV disease. This work shows how targeting NiV-F can be useful to preventing NiV disease, supporting future studies in the development of vaccines and therapeutics.
History
DepositionFeb 1, 2024-
Header (metadata) releaseSep 4, 2024-
Map releaseSep 4, 2024-
UpdateOct 30, 2024-
Current statusOct 30, 2024Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_19525.png

Downloads & links

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Map

FileDownload / File: emd_19525.map.gz / Format: CCP4 / Size: 91.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationNipah virus (NiV) fusion protein in complex with neutralizing Fab92
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.09 Å/pix.
x 288 pix.
= 312.48 Å		1.09 Å/pix.
x 288 pix.
= 312.48 Å		1.09 Å/pix.
x 288 pix.
= 312.48 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.085 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 1.29
Minimum - Maximum-4.1302977 - 6.113572
Average (Standard dev.)0.0043150284 (±0.114886515)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions288288288
Spacing288288288
CellA=B=C: 312.48 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_19525_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map B

Fileemd_19525_half_map_1.map
AnnotationHalf map B
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map A

Fileemd_19525_half_map_2.map
AnnotationHalf map A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Nipah virus fusion (F) glycoprotein in complex with Fab92

EntireName: Nipah virus fusion (F) glycoprotein in complex with Fab92
Components
  • Complex: Nipah virus fusion (F) glycoprotein in complex with Fab92
    • Protein or peptide: Fusion glycoprotein F0
    • Protein or peptide: Fab92 heavy chain
    • Protein or peptide: Fab92 light chain
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: Nipah virus fusion (F) glycoprotein in complex with Fab92

SupramoleculeName: Nipah virus fusion (F) glycoprotein in complex with Fab92
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Source (natural)Organism: Henipavirus nipahense

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Macromolecule #1: Fusion glycoprotein F0

MacromoleculeName: Fusion glycoprotein F0 / type: protein_or_peptide / ID: 1 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Henipavirus nipahense
Molecular weightTheoretical: 55.131039 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: GILHYEKLSK IGLVKGVTRK YKIKSNPLTK DIVIKMIPNV SNMSQCTGSV MENYKTRLNG ILTPIKGALE IYKNNTHDLV GDVRLAGVI MAGVAIGIAT AAQITAGVAL YEAMKNADNI NKLKSSIEST NEAVVKLQET AEKTVYVLTA LQDYINTNLV P TIDKISCK ...String:
GILHYEKLSK IGLVKGVTRK YKIKSNPLTK DIVIKMIPNV SNMSQCTGSV MENYKTRLNG ILTPIKGALE IYKNNTHDLV GDVRLAGVI MAGVAIGIAT AAQITAGVAL YEAMKNADNI NKLKSSIEST NEAVVKLQET AEKTVYVLTA LQDYINTNLV P TIDKISCK QTELSLDLAL SKYLSDLLFV FGPNLQDPVS NSMTIQAISQ AFGGNYETLL RTLGYATEDF DDLLESDSIT GQ IIYVDLS SYYIIVRVYF PILTEIQQAY IQELLPVSFN NDNSEWISIV PNFILVRNTL ISNIEIGFCL ITKRSVICNQ DYA TPMTNN MRECLTGSTE KCPRELVVSS HVPRFALSNG VLFANCISVT CQCQTTGRAI SQSGEQTLLM IDNTTCPTAV LGNV IISLG KYLGSVNYNS EGIAIGPPVF TDKVDISSQI SSMNQSLQQS KDYIKEAQRL LDGTMKQIED KIEEILSKIY HIENE IARI KKLIGEGGSH HHHHH

UniProtKB: Fusion glycoprotein F0

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Macromolecule #2: Fab92 heavy chain

MacromoleculeName: Fab92 heavy chain / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Oryctolagus cuniculus (rabbit)
Molecular weightTheoretical: 22.841697 KDa
SequenceString: QSLEESGGRL VTPGTPLTLT CTASGFSLSS YYMMWVRQAP GKGLEWIGII NTGGNAYYAS WTKGRFTISK TSTTVDLKIT SPTTEDTAT YFCARAVPSG AGYSAGGLWG PGTLVTVSSG QPKAPSVFPL APCCGDTPSS TVTLGCLVKG YLPEPVTVTW N SGTLTNGV ...String:
QSLEESGGRL VTPGTPLTLT CTASGFSLSS YYMMWVRQAP GKGLEWIGII NTGGNAYYAS WTKGRFTISK TSTTVDLKIT SPTTEDTAT YFCARAVPSG AGYSAGGLWG PGTLVTVSSG QPKAPSVFPL APCCGDTPSS TVTLGCLVKG YLPEPVTVTW N SGTLTNGV RTFPSVRQSS GLYSLSSVVS VTSSSQPVTC NVAHPATNTK VDKTVAPSTC NK

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Macromolecule #3: Fab92 light chain

MacromoleculeName: Fab92 light chain / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Oryctolagus cuniculus (rabbit)
Molecular weightTheoretical: 22.564949 KDa
SequenceString: DQVLTQTPAS VEAAVGGTVT IKCQASQSVG FYLSWYQQKP GQPPKLLIYR ASTLESGVPS RFKGSGSGTE FTLTISDLEC ADAATYYCQ TNDYLASSAF GGGTEVVVRG DPVAPTVLIF PPAADQVATG TVTIVCVANK YFPDVTVTWE VDGTTQTTGI E NSKTPQNS ...String:
DQVLTQTPAS VEAAVGGTVT IKCQASQSVG FYLSWYQQKP GQPPKLLIYR ASTLESGVPS RFKGSGSGTE FTLTISDLEC ADAATYYCQ TNDYLASSAF GGGTEVVVRG DPVAPTVLIF PPAADQVATG TVTIVCVANK YFPDVTVTWE VDGTTQTTGI E NSKTPQNS ADCTYNLSST LTLTSTQYNS HKEYTCKVTQ GTTSVVQSFS RKNC

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Macromolecule #4: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 4 / Number of copies: 12 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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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

BufferpH: 8
VitrificationCryogen name: ETHANE-PROPANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 44.37 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 3.7 µm / Nominal defocus min: 1.4000000000000001 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

6t3f

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 178307
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

6t3f


Chain - Source name: PDB / Chain - Initial model type: experimental model
RefinementProtocol: AB INITIO MODEL
Output model

PDB-8rvn:
Nipah virus (NiV) fusion protein in complex with neutralizing Fab92

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