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- PDB-8cw9: Prefusion-stabilized hMPV fusion protein bound to ADI-61026 and M... -

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Basic information

Entry
Database: PDB / ID: 8cw9
TitlePrefusion-stabilized hMPV fusion protein bound to ADI-61026 and MPE8 Fabs
Components
  • ADI-61026 heavy
  • ADI-61026 light
  • Fusion glycoprotein F0
  • MPE8 heavy chain
  • MPE8 light chain
KeywordsVIRAL PROTEIN/Immune System / Site 0 neutralizing antibody / Prefusion-stabilized hMPV F protein / VIRAL PROTEIN / VIRAL PROTEIN-Immune System complex
Function / homologyPrecursor fusion glycoprotein F0, Paramyxoviridae / Fusion glycoprotein F0 / fusion of virus membrane with host plasma membrane / host cell plasma membrane / virion membrane / plasma membrane / Fusion glycoprotein F0
Function and homology information
Biological speciesHuman metapneumovirus
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.46 Å
AuthorsHsieh, C.-L. / McLellan, J.S.
Funding support United States, 1items
OrganizationGrant numberCountry
Robert A. Welch FoundationF-0003-19620604 United States
CitationJournal: Immunity / Year: 2022
Title: Potently neutralizing and protective anti-human metapneumovirus antibodies target diverse sites on the fusion glycoprotein.
Authors: C Garrett Rappazzo / Ching-Lin Hsieh / Scott A Rush / Emma S Esterman / Teresa Delgado / James C Geoghegan / Anna Z Wec / Mrunal Sakharkar / Vicente Más / Jason S McLellan / Laura M Walker /
Abstract: Human metapneumovirus (hMPV) is a leading cause of acute lower respiratory tract infections in high-risk populations, yet there are no vaccines or anti-viral therapies approved for the prevention or ...Human metapneumovirus (hMPV) is a leading cause of acute lower respiratory tract infections in high-risk populations, yet there are no vaccines or anti-viral therapies approved for the prevention or treatment of hMPV-associated disease. Here, we used a high-throughput single-cell technology to interrogate memory B cell responses to the hMPV fusion (F) glycoprotein in young adult and elderly donors. Across all donors, the neutralizing antibody response was primarily directed to epitopes expressed on both pre- and post-fusion F conformations. However, we identified rare, highly potent broadly neutralizing antibodies that recognize pre-fusion-specific epitopes and structurally characterized an antibody that targets a site of vulnerability at the pre-fusion F trimer apex. Additionally, monotherapy with neutralizing antibodies targeting three distinct antigenic sites provided robust protection against lower respiratory tract infection in a small animal model. This study provides promising monoclonal antibody candidates for passive immunoprophylaxis and informs the rational design of hMPV vaccine immunogens.
History
DepositionMay 18, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 10, 2022Provider: repository / Type: Initial release
Revision 1.1Feb 22, 2023Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Fusion glycoprotein F0
B: MPE8 light chain
C: ADI-61026 heavy
D: ADI-61026 light
E: Fusion glycoprotein F0
F: Fusion glycoprotein F0
G: MPE8 heavy chain
H: ADI-61026 heavy
I: ADI-61026 heavy
J: MPE8 heavy chain
K: ADI-61026 light
L: ADI-61026 light
M: MPE8 light chain
N: MPE8 heavy chain
O: MPE8 light chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)541,47918
Polymers540,81515
Non-polymers6643
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Antibody , 4 types, 12 molecules BMOCHIDKLGJN

#2: Antibody MPE8 light chain


Mass: 22772.092 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#3: Antibody ADI-61026 heavy


Mass: 24699.928 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#4: Antibody ADI-61026 light


Mass: 22912.414 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#5: Antibody MPE8 heavy chain


Mass: 49433.516 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)

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Protein / Sugars , 2 types, 6 molecules AEF

#1: Protein Fusion glycoprotein F0 / Fusion glycoprotein F1 / Fusion glycoprotein F2


Mass: 60453.852 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human metapneumovirus / Production host: Homo sapiens (human) / References: UniProt: H6X1Z0
#6: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE / N-Acetylglucosamine


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Details

Has ligand of interestN

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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: hMPV fusion protein bound to ADI-61026 and MPE8 Fabs / Type: COMPLEX / Entity ID: #1-#5 / Source: RECOMBINANT
Source (natural)Organism: Human metapneumovirus
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 8
Details: 2 mM Tris pH 8.0, 200 mM NaCl, 0.02% NaN3, 0.075% amphipol
SpecimenConc.: 0.36 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Details: 0.36 mg/mL hMPV F (2 mM Tris pH 8.0, 200 mM NaCl, 0.02% NaN3, 0.075% amphipol) and 2-folds molar excess MPE8 and 1.5- folds molar excess ADI-61026
Specimen supportGrid material: COPPER / Grid mesh size: 400 divisions/in. / Grid type: C-flat-1.2/1.3
VitrificationCryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 283 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2500 nm / Nominal defocus min: 1500 nm / Cs: 2.7 mm
Image recordingElectron dose: 70 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.20_4459: / Classification: refinement
EM softwareName: SerialEM / Category: image acquisition
CTF correctionType: NONE
3D reconstructionResolution: 3.46 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 113336 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.002
ELECTRON MICROSCOPYf_angle_d0.656
ELECTRON MICROSCOPYf_dihedral_angle_d13.6687437
ELECTRON MICROSCOPYf_chiral_restr0.0463237
ELECTRON MICROSCOPYf_plane_restr0.013573

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