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- PDB-8uuq: Structure of the Measles virus Fusion protein in the pre-fusion c... -

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Basic information

Entry
Database: PDB / ID: 8uuq
TitleStructure of the Measles virus Fusion protein in the pre-fusion conformation with bound [FIP-HRC]2-PEG11
Components
  • (Fusion glycoprotein ...) x 2
  • [FIP-HRC]2-PEG11
KeywordsVIRAL PROTEIN / glycoprotein / immune system / measles / high-resolution / ectodomain / post-fusion / small molecule / inhibitor / complex
Function / homology
Function and homology information


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 speciesMeasles virus strain Ichinose-B95a
synthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.34 Å
AuthorsZyla, D. / Saphire, E.O.
Funding support Switzerland, United States, 5items
OrganizationGrant numberCountry
Swiss National Science FoundationP2EZP3_195680 Switzerland
Swiss National Science FoundationP500PB_210992 Switzerland
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)NS105699 United States
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)NS091263 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)AI176833 United States
CitationJournal: Science / Year: 2024
Title: A neutralizing antibody prevents postfusion transition of measles virus fusion protein.
Authors: Dawid S Zyla / Roberta Della Marca / Gele Niemeyer / Gillian Zipursky / Kyle Stearns / Cameron Leedale / Elizabeth B Sobolik / Heather M Callaway / Chitra Hariharan / Weiwei Peng / Diptiben ...Authors: Dawid S Zyla / Roberta Della Marca / Gele Niemeyer / Gillian Zipursky / Kyle Stearns / Cameron Leedale / Elizabeth B Sobolik / Heather M Callaway / Chitra Hariharan / Weiwei Peng / Diptiben Parekh / Tara C Marcink / Ruben Diaz Avalos / Branka Horvat / Cyrille Mathieu / Joost Snijder / Alexander L Greninger / Kathryn M Hastie / Stefan Niewiesk / Anne Moscona / Matteo Porotto / Erica Ollmann Saphire /
Abstract: Measles virus (MeV) presents a public health threat that is escalating as vaccine coverage in the general population declines and as populations of immunocompromised individuals, who cannot be ...Measles virus (MeV) presents a public health threat that is escalating as vaccine coverage in the general population declines and as populations of immunocompromised individuals, who cannot be vaccinated, increase. There are no approved therapeutics for MeV. Neutralizing antibodies targeting viral fusion are one potential therapeutic approach but have not yet been structurally characterized or advanced to clinical use. We present cryo-electron microscopy (cryo-EM) structures of prefusion F alone [2.1-angstrom (Å) resolution], F complexed with a fusion-inhibitory peptide (2.3-Å resolution), F complexed with the neutralizing and protective monoclonal antibody (mAb) 77 (2.6-Å resolution), and an additional structure of postfusion F (2.7-Å resolution). In vitro assays and examination of additional EM classes show that mAb 77 binds prefusion F, arrests F in an intermediate state, and prevents transition to the postfusion conformation. These structures shed light on antibody-mediated neutralization that involves arrest of fusion proteins in an intermediate state.
History
DepositionNov 1, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 3, 2024Provider: repository / Type: Initial release
Revision 1.1Jul 10, 2024Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _citation_author.name / _em_admin.last_update
Revision 1.2Jul 24, 2024Group: Data collection / Source and taxonomy / Structure summary
Category: em_admin / em_entity_assembly_naturalsource ...em_admin / em_entity_assembly_naturalsource / entity_src_gen / pdbx_molecule_features
Item: _em_admin.last_update / _em_entity_assembly_naturalsource.ncbi_tax_id ..._em_admin.last_update / _em_entity_assembly_naturalsource.ncbi_tax_id / _em_entity_assembly_naturalsource.organism / _entity_src_gen.gene_src_strain / _entity_src_gen.pdbx_gene_src_ncbi_taxonomy_id / _entity_src_gen.pdbx_gene_src_scientific_name
Revision 1.3Nov 13, 2024Group: Data collection / Structure summary
Category: em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Fusion glycoprotein F0
C: Fusion glycoprotein F0
D: Fusion glycoprotein F0
E: Fusion glycoprotein F0
F: Fusion glycoprotein F0
G: Fusion glycoprotein F0
M: [FIP-HRC]2-PEG11
N: [FIP-HRC]2-PEG11
O: [FIP-HRC]2-PEG11
hetero molecules


Theoretical massNumber of molelcules
Total (without water)178,53518
Polymers173,7039
Non-polymers4,8319
Water59433
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Fusion glycoprotein ... , 2 types, 6 molecules ADFCEG

#1: Protein Fusion glycoprotein F0


Mass: 12498.768 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Measles virus strain Ichinose-B95a / Cell line (production host): S2 / Production host: Drosophila melanogaster (fruit fly) / References: UniProt: Q786F3
#2: Protein Fusion glycoprotein F0


Mass: 44898.820 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Measles virus strain Ichinose-B95a / Cell line (production host): S2 / Production host: Drosophila melanogaster (fruit fly) / References: UniProt: Q786F3

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Protein/peptide / Non-polymers , 2 types, 36 molecules MNO

#3: Protein/peptide [FIP-HRC]2-PEG11


Type: Peptide-like / Class: Inhibitor / Mass: 503.546 Da / Num. of mol.: 3 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others) / References: BIRD: PRD_002539
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 33 / Source method: isolated from a natural source / Formula: H2O

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Sugars , 3 types, 9 molecules

#4: Polysaccharide
beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta- ...beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 586.542 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/2,3,2/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5]/1-1-2/a4-b1_b4-c1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{}}}}LINUCSPDB-CARE
#5: Polysaccharide alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2- ...alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 910.823 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-3[DManpa1-6]DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/3,5,4/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3-3/a4-b1_b4-c1_c3-d1_c6-e1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(3+1)][a-D-Manp]{}[(6+1)][a-D-Manp]{}}}}}LINUCSPDB-CARE
#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


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 interestY
Has protein modificationY

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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: Structure of the Measles virus Fusion protein in the pre-fusion conformation with bound [FIP-HRC]2-PEG11
Type: COMPLEX / Entity ID: #1-#3 / Source: RECOMBINANT
Molecular weightUnits: MEGADALTONS / Experimental value: NO
Source (natural)Organism: Measles virus strain Ichinose-B95a / Strain: Ichinose-B95a
Source (recombinant)Organism: Drosophila melanogaster (fruit fly) / Strain: S2
Buffer solutionpH: 8 / Details: HEPES 50 mM, pH 8.0, NaCl 150 mM
SpecimenConc.: 0.38 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 400 divisions/in. / Grid type: Quantifoil R2/2
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 298 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 FIELD / Nominal defocus max: 2500 nm / Nominal defocus min: 1000 nm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingAverage exposure time: 2 sec. / Electron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of grids imaged: 3 / Num. of real images: 10716

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Processing

EM software
IDNameVersionCategory
1cryoSPARC4.2particle selection
2RELION4particle selection
3EPUimage acquisition
5cryoSPARCCTF correction
6CTFFINDCTF correction
9UCSF ChimeraXmodel fitting
11cryoSPARCinitial Euler assignment
12RELIONinitial Euler assignment
13cryoSPARCfinal Euler assignment
14RELIONclassification
15cryoSPARCv4.23D reconstruction
16PHENIXmodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 3000000
3D reconstructionResolution: 2.34 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 235000 / Num. of class averages: 1 / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT / Space: REAL
Atomic model buildingPDB-ID: 5YXW

5yxw


Accession code: 5YXW / Source name: PDB / Type: experimental model
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 61.88 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.003510856
ELECTRON MICROSCOPYf_angle_d0.538214727
ELECTRON MICROSCOPYf_chiral_restr0.04541832
ELECTRON MICROSCOPYf_plane_restr0.0041845
ELECTRON MICROSCOPYf_dihedral_angle_d9.90311503

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