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- EMDB-27419: Cryo-EM Structure of RSV prefusion F trimer in complex with three... -

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Basic information

Entry
Database: EMDB / ID: EMD-27419
TitleCryo-EM Structure of RSV prefusion F trimer in complex with three MxR Fabs
Map dataSharp map to 2.2A resolution
Sample
  • Complex: Trimeric complex of three MxR Fabs bound to RSV preF protomer
    • Protein or peptide: Fusion glycoprotein F0
    • Protein or peptide: mAb MxR Heavy Chain, VH region
    • Protein or peptide: mAb MxR Light Chain, VL region
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
Biological speciesHomo sapiens (human) / Respiratory syncytial virus A2
Methodsingle particle reconstruction / cryo EM / Resolution: 2.24 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_27419.png

Downloads & links

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Map

FileDownload / File: emd_27419.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationSharp map to 2.2A resolution
Voxel sizeX=Y=Z: 1.02885 Å
Density
Contour LevelBy AUTHOR: 2.0
Minimum - Maximum-13.855747 - 21.13612
Average (Standard dev.)0.003105616 (±0.36764005)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions384384384
Spacing384384384
CellA=B=C: 395.07837 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_27419_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half Map A

Fileemd_27419_half_map_1.map
AnnotationHalf Map A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half Map B

Fileemd_27419_half_map_2.map
AnnotationHalf Map 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 : Trimeric complex of three MxR Fabs bound to RSV preF protomer

EntireName: Trimeric complex of three MxR Fabs bound to RSV preF protomer
Components
  • Complex: Trimeric complex of three MxR Fabs bound to RSV preF protomer
    • Protein or peptide: Fusion glycoprotein F0
    • Protein or peptide: mAb MxR Heavy Chain, VH region
    • Protein or peptide: mAb MxR Light Chain, VL region
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: Trimeric complex of three MxR Fabs bound to RSV preF protomer

SupramoleculeName: Trimeric complex of three MxR Fabs bound to RSV preF protomer
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: Respiratory syncytial virus A2
Molecular weightTheoretical: 63.526602 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MELLILKANA ITTILTAVTF CFASGQNITE EFYQSTCSAV SKGYLSALRT GWYTSVITIE LSNIKENKCN GTDAKVKLIK QELDKYKNA VTELQLLMQS TPATNNRARR ELPRFMNYTL NNAKKTNVTL SKKRKRRFLG FLLGVGSAIA SGVAVCKVLH L EGEVNKIK ...String:
MELLILKANA ITTILTAVTF CFASGQNITE EFYQSTCSAV SKGYLSALRT GWYTSVITIE LSNIKENKCN GTDAKVKLIK QELDKYKNA VTELQLLMQS TPATNNRARR ELPRFMNYTL NNAKKTNVTL SKKRKRRFLG FLLGVGSAIA SGVAVCKVLH L EGEVNKIK SALLSTNKAV VSLSNGVSVL TFKVLDLKNY IDKQLLPILN KQSCSISNIE TVIEFQQKNN RLLEITREFS VN AGVTTPV STYMLTNSEL LSLINDMPIT NDQKKLMSNN VQIVRQQSYS IMCIIKEEVL AYVVQLPLYG VIDTPCWKLH TSP LCTTNT KEGSNICLTR TDRGWYCDNA GSVSFFPQAE TCKVQSNRVF CDTMNSLTLP SEVNLCNVDI FNPKYDCKIM TSKT DVSSS VITSLGAIVS CYGKTKCTAS NKNRGIIKTF SNGCDYVSNK GVDTVSVGNT LYYVNKQEGK SLYVKGEPII NFYDP LVFP SDEFDASISQ VNEKINQSLA FIRKSDELLS AIGGYIPEAP RDGQAYVRKD GEWVLLSTFL GLNDIFEAQK IEWHEG SHH HHHHHH

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Macromolecule #2: mAb MxR Heavy Chain, VH region

MacromoleculeName: mAb MxR Heavy Chain, VH region / type: protein_or_peptide / ID: 2 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 12.952548 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
EVQVVESGGG LVKPGGSLRL SCAASGFPFS SYKMDWVRQA PGKGLEWVSS ISASGSYINY ADSVKGRFTI SRDNAKNSLY LQMKSLRAD DTAVYFCARD GGRELSPFEK WGQGILVTVS S

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Macromolecule #3: mAb MxR Light Chain, VL region

MacromoleculeName: mAb MxR Light Chain, VL region / type: protein_or_peptide / ID: 3 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 11.606782 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
QSVLTQPPSV SGAPGQRVTI SCTGTNSNIG TGYDVHWYQQ LPGTAPKVVL FDNNNRPSGV PDRFSGSKSG TSAALAITGL QAEDEAVYY CQSYDKSLGG WVFGGGTKLT VL

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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: 6 / 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

Concentration0.21 mg/mL
BufferpH: 7.5
GridModel: UltrAuFoil R1.2/1.3 / Material: GOLD / Mesh: 300 / 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
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 3.0 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.24 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 354922
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE
FSC plot (resolution estimation)

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