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- EMDB-27418: Cryo-EM Structure of HPIV3 prefusion F trimer in complex with 3x1 Fab -

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Basic information

Entry
Database: EMDB / ID: EMD-27418
TitleCryo-EM Structure of HPIV3 prefusion F trimer in complex with 3x1 Fab
Map dataSharpened map to 3.6A
Sample
  • Complex: Complex of one 3x1 Fab bound to the HPIV3 preF trimer
    • Protein or peptide: Fusion glycoprotein F0
    • Protein or peptide: 3x1 monoclonal antibody, VH region
    • Protein or peptide: 3x1 monoclonal antibody, VL region
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
Biological speciesHomo sapiens (human) / Human parainfluenza 3 virus (strain NIH 47885)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.62 Å
AuthorsRodarte JV / Pancera M
Funding support United States, 1 items
OrganizationGrant numberCountry
Other private United States
CitationJournal: Nat Commun / Year: 2023
Title: Cross-protective antibodies against common endemic respiratory viruses.
Authors: Madelyn Cabán / Justas V Rodarte / Madeleine Bibby / Matthew D Gray / Justin J Taylor / Marie Pancera / Jim Boonyaratanakornkit /
Abstract: Respiratory syncytial virus (RSV), human metapneumovirus (HMPV), and human parainfluenza virus types one (HPIV1) and three (HPIV3) can cause severe disease and death in immunocompromised patients, ...Respiratory syncytial virus (RSV), human metapneumovirus (HMPV), and human parainfluenza virus types one (HPIV1) and three (HPIV3) can cause severe disease and death in immunocompromised patients, the elderly, and those with underlying lung disease. A protective monoclonal antibody exists for RSV, but clinical use is limited to high-risk infant populations. Hence, therapeutic options for these viruses in vulnerable patient populations are currently limited. Here, we present the discovery, in vitro characterization, and in vivo efficacy testing of two cross-neutralizing monoclonal antibodies, one targeting both HPIV3 and HPIV1 and the other targeting both RSV and HMPV. The 3 × 1 antibody is capable of targeting multiple parainfluenza viruses; the MxR antibody shares features with other previously reported monoclonal antibodies that are capable of neutralizing both RSV and HMPV. We obtained structures using cryo-electron microscopy of these antibodies in complex with their antigens at 3.62 Å resolution for 3 × 1 bound to HPIV3 and at 2.24 Å for MxR bound to RSV, providing a structural basis for in vitro binding and neutralization. Together, a cocktail of 3 × 1 and MxR could have clinical utility in providing broad protection against four of the respiratory viruses that cause significant morbidity and mortality in at-risk individuals.
History
DepositionJun 23, 2022-
Header (metadata) releaseFeb 22, 2023-
Map releaseFeb 22, 2023-
UpdateFeb 22, 2023-
Current statusFeb 22, 2023Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_27418.png

Downloads & links

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Map

FileDownload / File: emd_27418.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationSharpened map to 3.6A
Voxel sizeX=Y=Z: 1.02885 Å
Density
Contour LevelBy AUTHOR: 0.8
Minimum - Maximum-10.400105 - 15.607214
Average (Standard dev.)0.0014667534 (±0.16680871)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 329.232 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_27418_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Halfmap A

Fileemd_27418_half_map_1.map
AnnotationHalfmap A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Halfmap B

Fileemd_27418_half_map_2.map
AnnotationHalfmap B
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 one 3x1 Fab bound to the HPIV3 preF trimer

EntireName: Complex of one 3x1 Fab bound to the HPIV3 preF trimer
Components
  • Complex: Complex of one 3x1 Fab bound to the HPIV3 preF trimer
    • Protein or peptide: Fusion glycoprotein F0
    • Protein or peptide: 3x1 monoclonal antibody, VH region
    • Protein or peptide: 3x1 monoclonal antibody, VL region
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: Complex of one 3x1 Fab bound to the HPIV3 preF trimer

SupramoleculeName: Complex of one 3x1 Fab bound to the HPIV3 preF trimer / type: complex / ID: 1 / Chimera: Yes / Parent: 0 / Macromolecule list: #1-#3
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 339 KDa

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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: Human parainfluenza 3 virus (strain NIH 47885)
Molecular weightTheoretical: 54.970625 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: QIDITKLQHV GVLVNSPKGM KISQNFETRY LILSLIPKIE DSNSCGDQQI KQYKRLLDRL IIPLYDGLKL QKDVIVTNQE SNENTDPRT ERFFGGVIGT IALGVATSAQ ITAAVALVEA KQAKSDIEKL KEAIRDTNKA VQSVCSSVGN CIVAIKSVQD Y VNKEIVPS ...String:
QIDITKLQHV GVLVNSPKGM KISQNFETRY LILSLIPKIE DSNSCGDQQI KQYKRLLDRL IIPLYDGLKL QKDVIVTNQE SNENTDPRT ERFFGGVIGT IALGVATSAQ ITAAVALVEA KQAKSDIEKL KEAIRDTNKA VQSVCSSVGN CIVAIKSVQD Y VNKEIVPS IARLGCEAAG LQLGIALTQH YSELTNCFGD NIGSLQEKGI KLQCIASLYR TNITEIFTTS TVDKYDIYDL LF TESIKVR VIDVDLNDYS ITLQVRLPLL TRLLNTQIYK VDSISYNIQN REWYIPLPSH IMTKGAFLGG ADVKECIEAF SSY ICPSDP GFVLNHEMES CLSGNISQCP RTTVTSDIVP RYAFVNGGVV ANCITTTCTC NGIGNRINQP PDQGVKIITH KECN TIGIN GMLFNTNKEG TLAFYTPDDI TLNNSVALDP IDISIELNKV KSDLEESKEW YRRSNQKLSA IEDKIEEILS KIYHI ENEI ARIKKLIGEA P

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Macromolecule #2: 3x1 monoclonal antibody, VH region

MacromoleculeName: 3x1 monoclonal antibody, VH region / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 13.932664 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
EVQLLESGGG LVQPGGSLRL SCAASGFTFS SFGMSWVRQS PGKGLEWVAD ISHSAGFLNY ADSVKGRFTV SRDNSKSTLH LQMKSLRAE DTAVYYCAKR LAGLPDLEWL LYPNFLDHWG QGTLVTVSS

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Macromolecule #3: 3x1 monoclonal antibody, VL region

MacromoleculeName: 3x1 monoclonal antibody, VL region / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 11.642857 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
SSELTQDPAV SVALGQTVRI TCQGDILRTY YVSWYQQKPG QAPLLVIYGK NNRPSVIPDR FSGSTSGDTA SLTITGAQAE DEAEYYCSS RDRSGNHVLF GGGTKLTVL

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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: 9 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

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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

Concentration0.19 mg/mL
BufferpH: 7.5
GridModel: UltrAuFoil R1.2/1.3 / Material: GOLD / Mesh: 200 / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 295 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 3.5 µm / Nominal defocus min: 0.5 µm
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.0 e/Å2 / Details: Collected at 30 degree tilt
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.62 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 1036244
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementSpace: REAL
Output model

PDB-8dg8:
Cryo-EM Structure of HPIV3 prefusion F trimer in complex with 3x1 Fab

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