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- PDB-7tn1: Multistate design to stabilize viral class I fusion proteins -

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Basic information

Entry
Database: PDB / ID: 7tn1
TitleMultistate design to stabilize viral class I fusion proteins
ComponentsFusion glycoprotein F0
KeywordsVIRAL PROTEIN / Respiratory syncytial virus / Fusion protein
Function / homology
Function and homology information


symbiont-mediated induction of syncytium formation / host cell Golgi membrane / entry receptor-mediated virion attachment to host cell / fusion of virus membrane with host plasma membrane / host cell plasma membrane / virion membrane / plasma membrane
Similarity search - Function
Precursor fusion glycoprotein F0, Paramyxoviridae / Fusion glycoprotein F0
Similarity search - Domain/homology
Fusion glycoprotein F0
Similarity search - Component
Biological speciesRespiratory syncytial virus
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.1 Å
AuthorsHuang, J. / Banerjee, A. / Gonzalez, K. / Mousa, J. / Strauch, E.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R01AI140245 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R01AI143865 United States
Citation
Journal: Nat Commun / Year: 2024
Title: A general computational design strategy for stabilizing viral class I fusion proteins.
Authors: Karen J Gonzalez / Jiachen Huang / Miria F Criado / Avik Banerjee / Stephen M Tompkins / Jarrod J Mousa / Eva-Maria Strauch /
Abstract: Many pathogenic viruses rely on class I fusion proteins to fuse their viral membrane with the host cell membrane. To drive the fusion process, class I fusion proteins undergo an irreversible ...Many pathogenic viruses rely on class I fusion proteins to fuse their viral membrane with the host cell membrane. To drive the fusion process, class I fusion proteins undergo an irreversible conformational change from a metastable prefusion state to an energetically more stable postfusion state. Mounting evidence underscores that antibodies targeting the prefusion conformation are the most potent, making it a compelling vaccine candidate. Here, we establish a computational design protocol that stabilizes the prefusion state while destabilizing the postfusion conformation. With this protocol, we stabilize the fusion proteins of the RSV, hMPV, and SARS-CoV-2 viruses, testing fewer than a handful of designs. The solved structures of these designed proteins from all three viruses evidence the atomic accuracy of our approach. Furthermore, the humoral response of the redesigned RSV F protein compares to that of the recently approved vaccine in a mouse model. While the parallel design of two conformations allows the identification of energetically sub-optimal positions for one conformation, our protocol also reveals diverse molecular strategies for stabilization. Given the clinical significance of viruses using class I fusion proteins, our algorithm can substantially contribute to vaccine development by reducing the time and resources needed to optimize these immunogens.
#1: Journal: Acta Crystallogr D Biol Crystallogr / Year: 2012
Title: Towards automated crystallographic structure refinement with phenix.refine.
Authors: Afonine, P.V. / Grosse-Kunstleve, R.W. / Echols, N. / Headd, J.J. / Moriarty, N.W. / Mustyakimov, M. / Terwilliger, T.C. / Urzhumtsev, A. / Zwart, P.H. / Adams, P.D.
History
DepositionJan 20, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 12, 2023Provider: repository / Type: Initial release
Revision 1.1Oct 25, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.2Jul 24, 2024Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _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
Revision 1.3Nov 20, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _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
F: Fusion glycoprotein F0
A: Fusion glycoprotein F0
B: Fusion glycoprotein F0
hetero molecules


Theoretical massNumber of molelcules
Total (without water)190,2596
Polymers189,5953
Non-polymers6643
Water543
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area10440 Å2
ΔGint-22 kcal/mol
Surface area57360 Å2
MethodPISA
Unit cell
Length a, b, c (Å)170.468, 170.468, 171.152
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number92
Space group name H-MP41212
Space group name HallP4abw2nw
Symmetry operation#1: x,y,z
#2: -y+1/2,x+1/2,z+1/4
#3: y+1/2,-x+1/2,z+3/4
#4: x+1/2,-y+1/2,-z+3/4
#5: -x+1/2,y+1/2,-z+1/4
#6: -x,-y,z+1/2
#7: y,x,-z
#8: -y,-x,-z+1/2

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Components

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


Mass: 63198.398 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Respiratory syncytial virus / Cell line (production host): 293 / Production host: Homo sapiens (human) / References: UniProt: W8RJF9
#2: 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
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 3 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestN
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 3.28 Å3/Da / Density % sol: 62.49 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop / Details: 0.2 M Sodium formate, 20% w/v PEG 3,350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-ID / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Apr 18, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3.1→49.28 Å / Num. obs: 44788 / % possible obs: 96.04 % / Redundancy: 6.4 % / Biso Wilson estimate: 78.22 Å2 / CC1/2: 0.981 / CC star: 0.995 / Net I/σ(I): 6.32
Reflection shellResolution: 3.1→3.211 Å / Redundancy: 7.2 % / Rmerge(I) obs: 1.336 / Mean I/σ(I) obs: 1.72 / Num. unique obs: 4518 / CC1/2: 0.518 / CC star: 0.826 / % possible all: 99.47

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Processing

Software
NameVersionClassification
PHENIX1.17.1_3660refinement
XDSdata reduction
Aimlessdata scaling
PHENIXphasing
Cootmodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5C6B

5c6b


Resolution: 3.1→49.28 Å / SU ML: 0.5077 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 30.9922
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.3151 1986 4.47 %
Rwork0.2535 42464 -
obs0.2563 44450 96.08 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 70.17 Å2
Refinement stepCycle: LAST / Resolution: 3.1→49.28 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10418 0 42 3 10463
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.010410618
X-RAY DIFFRACTIONf_angle_d1.282914422
X-RAY DIFFRACTIONf_chiral_restr0.07251768
X-RAY DIFFRACTIONf_plane_restr0.00741819
X-RAY DIFFRACTIONf_dihedral_angle_d15.44273873
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.1-3.180.35681460.30043075X-RAY DIFFRACTION99.54
3.18-3.260.38161420.28823085X-RAY DIFFRACTION99.45
3.26-3.360.31381420.27173087X-RAY DIFFRACTION99.42
3.36-3.470.31681470.25743078X-RAY DIFFRACTION99.08
3.47-3.590.32241420.25793082X-RAY DIFFRACTION99.02
3.59-3.740.35061450.25463061X-RAY DIFFRACTION97.8
3.74-3.910.30621430.24683010X-RAY DIFFRACTION96.25
3.91-4.110.29351400.23272989X-RAY DIFFRACTION95.66
4.11-4.370.30121390.22472997X-RAY DIFFRACTION95.17
4.37-4.710.24221390.20452994X-RAY DIFFRACTION94.82
4.71-5.180.27061390.21492984X-RAY DIFFRACTION94.01
5.18-5.930.31071340.26082983X-RAY DIFFRACTION93.46
5.93-7.460.3231440.28462927X-RAY DIFFRACTION90.8
7.46-49.280.36071440.28323112X-RAY DIFFRACTION91.49

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