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- PDB-8wsp: Crystal structure of SFTSV Gn and antibody SF5 -

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Basic information

Entry
Database: PDB / ID: 8wsp
TitleCrystal structure of SFTSV Gn and antibody SF5
Components
  • Ab5-H
  • Ab5-L
  • Gn
KeywordsVIRAL PROTEIN/IMMUNE SYSTEM / Virus / Antibody / VIRAL PROTEIN-IMMUNE SYSTEM complex
Function / homology
Function and homology information


host cell Golgi membrane / host cell endoplasmic reticulum membrane / fusion of virus membrane with host endosome membrane / symbiont entry into host cell / virion attachment to host cell / virion membrane / membrane
Similarity search - Function
Phlebovirus glycoprotein G1 / Phlebovirus glycoprotein G1 / Phlebovirus glycoprotein G2, fusion domain / Phlebovirus glycoprotein G2, C-terminal domain / Phlebovirus glycoprotein G2 fusion domain / Phlebovirus glycoprotein G2 C-terminal domain
Similarity search - Domain/homology
Envelopment polyprotein
Similarity search - Component
Biological speciesSFTS virus SD4
Homo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.51 Å
AuthorsChang, Z. / Gao, F. / Wu, Y.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)32090014 China
CitationJournal: Proc Natl Acad Sci U S A / Year: 2024
Title: Bispecific antibodies targeting two glycoproteins on SFTSV exhibit synergistic neutralization and protection in a mouse model.
Authors: Zhen Chang / Dan Gao / Liying Liao / Junqing Sun / Gen Zhang / Xue Zhang / Feiran Wang / Chunrui Li / Babayemi Olawale Oladejo / Shihua Li / Yan Chai / Yongfei Hu / Xuancheng Lu / Haixia ...Authors: Zhen Chang / Dan Gao / Liying Liao / Junqing Sun / Gen Zhang / Xue Zhang / Feiran Wang / Chunrui Li / Babayemi Olawale Oladejo / Shihua Li / Yan Chai / Yongfei Hu / Xuancheng Lu / Haixia Xiao / Jianxun Qi / Zhihai Chen / Feng Gao / Yan Wu /
Abstract: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease with a high fatality rate of up to 30% caused by SFTS virus (SFTSV). However, no specific vaccine or antiviral ...Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease with a high fatality rate of up to 30% caused by SFTS virus (SFTSV). However, no specific vaccine or antiviral therapy has been approved for clinical use. To develop an effective treatment, we isolated a panel of human monoclonal antibodies (mAbs). SF5 and SF83 are two neutralizing mAbs that recognize two viral glycoproteins (Gn and Gc), respectively. We found that their epitopes are closely located, and we then engineered them as several bispecific antibodies (bsAbs). Neutralization and animal experiments indicated that bsAbs display more potent protective effects than the parental mAbs, and the cryoelectron microscopy structure of a bsAb3 Fab-Gn-Gc complex elucidated the mechanism of protection. In vivo virus passage in the presence of antibodies indicated that two bsAbs resulted in less selective pressure and could efficiently bind to all single parental mAb-escape mutants. Furthermore, epitope analysis of the protective mAbs against SFTSV and RVFV indicated that they are all located on the Gn subdomain I, where may be the hot spots in the phleboviruses. Collectively, these data provide potential therapeutic agents and molecular basis for the rational design of vaccines against SFTSV infection.
History
DepositionOct 17, 2023Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Jun 12, 2024Provider: repository / Type: Initial release
Revision 1.1Oct 23, 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
A: Gn
B: Ab5-H
C: Ab5-L
D: Gn
E: Ab5-H
F: Ab5-L
hetero molecules


Theoretical massNumber of molelcules
Total (without water)169,13310
Polymers167,1116
Non-polymers2,0224
Water11,205622
1
A: Gn
B: Ab5-H
C: Ab5-L
hetero molecules


Theoretical massNumber of molelcules
Total (without water)84,5665
Polymers83,5563
Non-polymers1,0112
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
D: Gn
E: Ab5-H
F: Ab5-L
hetero molecules


Theoretical massNumber of molelcules
Total (without water)84,5665
Polymers83,5563
Non-polymers1,0112
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)94.876, 111.331, 191.926
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
d_1ens_1(chain "A" and (resid 16 through 293 or resid 302...
d_2ens_1chain "D"
d_1ens_2(chain "B" and (resid 1 through 132 or resid 145 through 224))
d_2ens_2chain "E"
d_1ens_3(chain "C" and resid 3 through 211)
d_2ens_3chain "F"

NCS domain segments:
Dom-IDComponent-IDEns-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
d_11ens_1ASPASPGLUGLUAA16 - 2931 - 278
d_12ens_1LYSLYSVALVALAA302 - 339287 - 324
d_13ens_1NAGNAGNAGNAGGG1
d_14ens_1NAGNAGNAGNAGGG2
d_15ens_1MANMANMANMANGG3
d_16ens_1NAGNAGNAGNAGHH1
d_17ens_1NAGNAGNAGNAGHH2
d_21ens_1ASPASPVALVALDD16 - 3391 - 324
d_22ens_1NAGNAGNAGNAGII1
d_23ens_1NAGNAGNAGNAGII2
d_24ens_1MANMANMANMANII3
d_25ens_1NAGNAGNAGNAGJJ1
d_26ens_1NAGNAGNAGNAGJJ2
d_11ens_2GLUGLUPHEPHEBB1 - 1321 - 132
d_12ens_2THRTHRLYSLYSBB145 - 224145 - 224
d_21ens_2GLUGLULYSLYSEE1 - 2241 - 224
d_11ens_3GLUGLUTHRTHRCC3 - 2113 - 211
d_21ens_3GLUGLUTHRTHRFF3 - 2113 - 211

NCS ensembles :
ID
ens_1
ens_2
ens_3

NCS oper:
IDCodeMatrixVector
1given(0.994788868025, 0.0958316048826, -0.0348053380953), (-0.0955358225306, 0.995375076571, 0.0100679469315), (0.035609193584, -0.00669032492793, 0.999343396878)45.2075857516, 10.5193676437, -1.56790264947
2given(0.998736325815, 0.00687381127986, -0.0497845580016), (-0.00817277423399, 0.999630214817, -0.0259352923016), (0.0495878741049, 0.0263093964951, 0.998423186028)43.6225524279, 5.66916325938, -1.74465547801
3given(0.996474232377, -0.0115995093866, -0.0830936555366), (0.00844102334263, 0.999232084678, -0.038262123254), (0.0834736685032, 0.0374258244127, 0.995806936275)42.6645782371, 4.53440371139, -3.38317345781

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Components

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Antibody , 2 types, 4 molecules BECF

#2: Antibody Ab5-H


Mass: 24227.232 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#3: Antibody Ab5-L


Mass: 22718.973 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)

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Protein / Non-polymers , 2 types, 624 molecules AD

#1: Protein Gn


Mass: 36609.332 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) SFTS virus SD4 / Production host: Homo sapiens (human) / References: UniProt: F1BDJ0
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 622 / Source method: isolated from a natural source / Formula: H2O

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Sugars , 2 types, 4 molecules

#4: Polysaccharide alpha-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta- ...alpha-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.: 2
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-4DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/2,3,2/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1a_1-5]/1-1-2/a4-b1_b4-c1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][a-D-Manp]{}}}}LINUCSPDB-CARE
#5: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}}LINUCSPDB-CARE

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Details

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: 3.03 Å3/Da / Density % sol: 59.44 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 6
Details: 0.1 M MES monohydrate pH6.0, 14% w/v Polyethylene glycol 4000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL19U1 / Wavelength: 0.97776 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Aug 28, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97776 Å / Relative weight: 1
ReflectionResolution: 2.5→50 Å / Num. obs: 69357 / % possible obs: 99.9 % / Redundancy: 6.1 % / Biso Wilson estimate: 36.09 Å2 / CC1/2: 0.99 / Rpim(I) all: 0.044 / Net I/σ(I): 15.9
Reflection shellResolution: 2.5→2.54 Å / Redundancy: 6.2 % / Mean I/σ(I) obs: 2.2 / Num. unique obs: 3415 / CC1/2: 0.655 / Rpim(I) all: 0.418 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
PHENIX1.20.1_4487refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.51→48.01 Å / SU ML: 0.3261 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 25.0378
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.243 3472 5.05 %
Rwork0.1954 65316 -
obs0.1979 68788 98.5 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 47.49 Å2
Refinement stepCycle: LAST / Resolution: 2.51→48.01 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms11238 0 134 622 11994
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.009411644
X-RAY DIFFRACTIONf_angle_d1.097415799
X-RAY DIFFRACTIONf_chiral_restr0.05861754
X-RAY DIFFRACTIONf_plane_restr0.00922019
X-RAY DIFFRACTIONf_dihedral_angle_d7.54221650
Refine LS restraints NCS
Ens-IDDom-IDAsym-IDAuth asym-IDRefine-IDTypeRms dev position (Å)
ens_1d_2AAX-RAY DIFFRACTIONTorsion NCS0.640437921007
ens_2d_2BBX-RAY DIFFRACTIONTorsion NCS0.965281220625
ens_3d_2CCX-RAY DIFFRACTIONTorsion NCS1.27012143143
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.51-2.550.3631990.28992074X-RAY DIFFRACTION79.22
2.55-2.590.33381310.26582526X-RAY DIFFRACTION96.44
2.59-2.620.28731330.2382571X-RAY DIFFRACTION97.86
2.62-2.660.27641440.24052584X-RAY DIFFRACTION99.02
2.66-2.710.27591260.23172620X-RAY DIFFRACTION98.78
2.71-2.760.28921460.22152584X-RAY DIFFRACTION99.2
2.76-2.810.25071460.222601X-RAY DIFFRACTION99.28
2.81-2.860.28211210.21612621X-RAY DIFFRACTION99.38
2.86-2.920.27421520.22392599X-RAY DIFFRACTION99.49
2.92-2.980.30021420.23112604X-RAY DIFFRACTION99.64
2.98-3.050.27751410.22692629X-RAY DIFFRACTION99.57
3.05-3.130.28091230.23222612X-RAY DIFFRACTION99.64
3.13-3.210.28761370.23642638X-RAY DIFFRACTION99.82
3.21-3.310.28541390.22062637X-RAY DIFFRACTION99.96
3.31-3.410.24091300.19382656X-RAY DIFFRACTION99.75
3.41-3.530.22281500.19462611X-RAY DIFFRACTION99.86
3.53-3.680.26591300.18712665X-RAY DIFFRACTION99.75
3.68-3.840.24331480.18382659X-RAY DIFFRACTION99.82
3.84-4.050.22781420.18072624X-RAY DIFFRACTION99.86
4.05-4.30.2161510.15952685X-RAY DIFFRACTION99.93
4.3-4.630.18341460.14342637X-RAY DIFFRACTION99.61
4.63-5.10.18591550.14342658X-RAY DIFFRACTION99.5
5.1-5.830.23331430.16442698X-RAY DIFFRACTION99.37
5.83-7.340.23061570.19572723X-RAY DIFFRACTION99.72
7.34-48.010.2131400.20132800X-RAY DIFFRACTION97.87
Refinement TLS params.Method: refined / Origin x: 67.4099871017 Å / Origin y: -7.72191660605 Å / Origin z: -26.0613218846 Å
111213212223313233
T0.260324744843 Å2-0.0486460395206 Å20.00851532057671 Å2-0.310623993926 Å2-0.0512840429462 Å2--0.263939010373 Å2
L0.14004016977 °2-0.0950527151179 °20.0398496862151 °2-0.228588986071 °2-0.0175756910878 °2--0.340259365761 °2
S0.0346752340332 Å °0.0446380632417 Å °-0.0685714160952 Å °0.0374006117094 Å °-0.0223943767753 Å °0.0390641572161 Å °0.0864964017218 Å °6.73523770023E-5 Å °-0.00778661008099 Å °
Refinement TLS groupSelection details: all

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