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- PDB-7uj3: Crystal structure of Human respiratory syncytial virus F variant ... -

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Basic information

Entry
Database: PDB / ID: 7uj3
TitleCrystal structure of Human respiratory syncytial virus F variant (construct pXCS847A)
Components
  • RSV variant (construct pXCS847A) F1
  • RSV variant (construct pXCS847A) F2
KeywordsVIRUS / RSV / RSVF / pre-fusion
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 speciesRespiratory syncytial virus
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.5 Å
AuthorsHan, S. / Ammirati, M.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Sci Transl Med / Year: 2023
Title: Rational design of a highly immunogenic prefusion-stabilized F glycoprotein antigen for a respiratory syncytial virus vaccine.
Authors: Ye Che / Alexey V Gribenko / Xi Song / Luke D Handke / Kari S Efferen / Kristin Tompkins / Srinivas Kodali / Lorna Nunez / A Krishna Prasad / Lynn M Phelan / Mark Ammirati / Xiaodi Yu / ...Authors: Ye Che / Alexey V Gribenko / Xi Song / Luke D Handke / Kari S Efferen / Kristin Tompkins / Srinivas Kodali / Lorna Nunez / A Krishna Prasad / Lynn M Phelan / Mark Ammirati / Xiaodi Yu / Joshua A Lees / Wei Chen / Lyndsey Martinez / Vidia Roopchand / Seungil Han / Xiayang Qiu / John P DeVincenzo / Kathrin U Jansen / Philip R Dormitzer / Kena A Swanson /
Abstract: Respiratory syncytial virus (RSV) is the leading, global cause of serious respiratory disease in infants and is an important cause of respiratory illness in older adults. No RSV vaccine is currently ...Respiratory syncytial virus (RSV) is the leading, global cause of serious respiratory disease in infants and is an important cause of respiratory illness in older adults. No RSV vaccine is currently available. The RSV fusion (F) glycoprotein is a key antigen for vaccine development, and its prefusion conformation is the target of the most potent neutralizing antibodies. Here, we describe a computational and experimental strategy for designing immunogens that enhance the conformational stability and immunogenicity of RSV prefusion F. We obtained an optimized vaccine antigen after screening nearly 400 engineered F constructs. Through in vitro and in vivo characterization studies, we identified F constructs that are more stable in the prefusion conformation and elicit ~10-fold higher serum-neutralizing titers in cotton rats than DS-Cav1. The stabilizing mutations of the lead construct (847) were introduced onto F glycoprotein backbones of strains representing the dominant circulating genotypes of the two major RSV subgroups, A and B. Immunization of cotton rats with a bivalent vaccine formulation of these antigens conferred complete protection against RSV challenge, with no evidence of disease enhancement. The resulting bivalent RSV prefusion F investigational vaccine has recently been shown to be efficacious against RSV disease in two pivotal phase 3 efficacy trials, one for passive protection of infants by immunization of pregnant women and the second for active protection of older adults by direct immunization.
History
DepositionMar 30, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 19, 2023Provider: repository / Type: Initial release
Revision 1.1May 10, 2023Group: Database references / Category: citation / Item: _citation.journal_volume / _citation.title
Revision 1.2Oct 25, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: RSV variant (construct pXCS847A) F2
B: RSV variant (construct pXCS847A) F1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)57,6456
Polymers57,1352
Non-polymers5094
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)170.020, 170.020, 170.020
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number213
Space group name H-MP4132

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Components

#1: Protein RSV variant (construct pXCS847A) F2


Mass: 12109.954 Da / Num. of mol.: 1 / Mutation: A100C
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Respiratory syncytial virus / Production host: Mammalia (mammals) / References: UniProt: A0A7D5GVC1
#2: Protein RSV variant (construct pXCS847A) F1


Mass: 45025.391 Da / Num. of mol.: 1 / Mutation: I145S, S187I, D483S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Respiratory syncytial virus / Production host: Mammalia (mammals) / References: UniProt: A0A7D5GVC1
#3: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#4: 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.: 1 / 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
Has ligand of interestN

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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: 3.58 Å3/Da / Density % sol: 65.68 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 0.1 M Na acetate, pH 4.6, 0.2 M ammonium sulfate, and 30% poly(ethylene) glycol monomethyl ether 2000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 1, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3.5→49.08 Å / Num. obs: 11179 / % possible obs: 99.8 % / Redundancy: 38.3 % / CC1/2: 1 / Net I/σ(I): 28.2
Reflection shellResolution: 3.5→3.71 Å / Num. unique obs: 1742 / CC1/2: 0.774

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Processing

Software
NameVersionClassification
BUSTER2.11.6refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
HKL-2000data scaling
BUSTERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4MMU

4mmu


Resolution: 3.5→49.08 Å / Cor.coef. Fo:Fc: 0.7211 / Cor.coef. Fo:Fc free: 0.64 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.513
RfactorNum. reflection% reflectionSelection details
Rfree0.2644 558 5.02 %RANDOM
Rwork0.236 ---
obs0.2374 11113 100 %-
Displacement parametersBiso max: 298.47 Å2 / Biso mean: 77.61 Å2 / Biso min: 9.48 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å20 Å2
2--0 Å20 Å2
3---0 Å2
Refine analyzeLuzzati coordinate error obs: 0.512 Å
Refinement stepCycle: final / Resolution: 3.5→49.08 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3392 0 29 0 3421
Biso mean--169.31 --
Num. residues----439
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1221SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes88HARMONIC2
X-RAY DIFFRACTIONt_gen_planes484HARMONIC5
X-RAY DIFFRACTIONt_it3474HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion490SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact3979SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d3474HARMONIC20.008
X-RAY DIFFRACTIONt_angle_deg4714HARMONIC21.12
X-RAY DIFFRACTIONt_omega_torsion2.1
X-RAY DIFFRACTIONt_other_torsion22.84
LS refinement shellResolution: 3.5→3.83 Å / Rfactor Rfree error: 0 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.2922 129 5.01 %
Rwork0.259 2447 -
all0.2607 2576 -
obs--100 %
Refinement TLS params.

L11: 0 °2 / Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
1-0.20370.27630.43531.12490.9649-0.0066-0.3029-0.20630.16810.33570.44810.2665-0.0566-0.32910.308-0.1548-0.1603-0.2151-0.1495-0.0471175.572162.644176.838
2-0.05510.210.30630.38091.6195-0.0956-0.2150.00720.27380.2720.16520.2613-0.1492-0.17630.0262-0.1021-0.1177-0.0832-0.02050.1212176.648172.916190.418
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A26 - 107
2X-RAY DIFFRACTION2{ B|* }B137 - 509

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