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- PDB-8wsu: Crystal structure of SFTSV Gc and antibody -

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Basic information

Entry
Database: PDB / ID: 8wsu
TitleCrystal structure of SFTSV Gc and antibody
Components
  • Ab-H
  • Ab-L
  • Glycoprotein C
KeywordsVIRAL PROTEIN/IMMUNE SYSTEM / Virus / Antibody / VIRAL PROTEIN-IMMUNE SYSTEM complex
Function / homology
Function and homology information


host cell Golgi membrane / entry receptor-mediated virion attachment to host cell / host cell endoplasmic reticulum membrane / symbiont entry into host cell / fusion of virus membrane with host endosome membrane / 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 phlebovirus
Homo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.3 Å
AuthorsChang, Z. / Gao, F. / Wu, Y.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)0009-0006-6123-817X 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Glycoprotein C
B: Ab-H
C: Ab-L
D: Glycoprotein C
E: Ab-H
F: Ab-L


Theoretical massNumber of molelcules
Total (without water)188,6366
Polymers188,6366
Non-polymers00
Water00
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)229.515, 72.053, 112.360
Angle α, β, γ (deg.)90.000, 111.470, 90.000
Int Tables number5
Space group name H-MC121
Space group name HallC2y
Symmetry operation#1: x,y,z
#2: -x,y,-z
#3: x+1/2,y+1/2,z
#4: -x+1/2,y+1/2,-z
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
d_1ens_1chain "A"
d_2ens_1chain "D"
d_1ens_2chain "B"
d_2ens_2chain "E"
d_1ens_3chain "C"
d_2ens_3chain "F"

NCS domain segments:

Component-ID: 1

Dom-IDEns-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
d_1ens_1LEULEUALAALAAA627 - 85665 - 294
d_2ens_1LEULEUALAALADD627 - 85665 - 294
d_1ens_2GLNGLNLYSLYSBB1 - 2241 - 224
d_2ens_2GLNGLNLYSLYSEE1 - 2241 - 224
d_1ens_3ASPASPCYSCYSCC1 - 2141 - 214
d_2ens_3ASPASPCYSCYSFF1 - 2141 - 214

NCS ensembles :
ID
ens_1
ens_2
ens_3

NCS oper:
IDCodeMatrixVector
1given(-0.999084189207, 0.00514405167502, -0.0424773069881), (-0.00482112903979, -0.99995872339, -0.00770118379488), (-0.0425151689562, -0.00748934238939, 0.999067750535)-38.5063236664, 0.226571991572, -3.1609053607
2given(-0.99981290772, 0.0163843087298, -0.0102812443128), (-0.0167167939044, -0.99931115417, 0.0331325512688), (-0.00973130817154, 0.0332982218665, 0.999398083879)-38.8227506134, -1.2593891839, -0.922262516011
3given(-0.999761361469, 0.0132990299052, -0.0173307794688), (-0.0140949962017, -0.998812063406, 0.0466453971706), (-0.0166898530697, 0.0468785430524, 0.998761158138)-38.737022762, -1.25520753552, -0.843951805041

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Components

#1: Protein Glycoprotein C / Gc / Glycoprotein G2


Mass: 47204.645 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) SFTS phlebovirus (isolate SFTSV/Human/China/HB29/2010)
Gene: GP / Production host: Homo sapiens (human) / References: UniProt: A0A0B5A886
#2: Antibody Ab-H


Mass: 23968.771 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 Ab-L


Mass: 23144.668 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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Experimental details

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Experiment

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

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Sample preparation

CrystalDensity Matthews: 2.29 Å3/Da / Density % sol: 46.33 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 7.8
Details: 0.1M Tris, pH7.8, 5% w/v gamma-PGA (Na+ form, LM), 15% w/v PEG 4000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL02U1 / Wavelength: 1.03879 Å
DetectorType: DECTRIS EIGER2 S 9M / Detector: PIXEL / Date: Nov 14, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.03879 Å / Relative weight: 1
ReflectionResolution: 3.3→50 Å / Num. obs: 25148 / % possible obs: 95.3 % / Redundancy: 7.9 % / Biso Wilson estimate: 83.22 Å2 / CC1/2: 0.984 / Rpim(I) all: 0.079 / Net I/σ(I): 8
Reflection shellResolution: 3.3→3.42 Å / Redundancy: 5.6 % / Mean I/σ(I) obs: 1.2 / Num. unique obs: 2106 / CC1/2: 0.641 / Rpim(I) all: 0.444 / % possible all: 80.5

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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: 3.3→36.03 Å / SU ML: 0.4903 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 31.7836
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2674 1204 4.98 %
Rwork0.207 22966 -
obs0.2101 24170 92.79 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 110.93 Å2
Refinement stepCycle: LAST / Resolution: 3.3→36.03 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9442 0 0 0 9442
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01219654
X-RAY DIFFRACTIONf_angle_d1.580413098
X-RAY DIFFRACTIONf_chiral_restr0.07661454
X-RAY DIFFRACTIONf_plane_restr0.01141680
X-RAY DIFFRACTIONf_dihedral_angle_d7.55181332
Refine LS restraints NCS
Ens-IDDom-IDAsym-IDAuth asym-IDRefine-IDTypeRms dev position (Å)
ens_1d_2AAX-RAY DIFFRACTIONTorsion NCS0.991804847523
ens_2d_2BBX-RAY DIFFRACTIONTorsion NCS0.688517158334
ens_3d_2CCX-RAY DIFFRACTIONTorsion NCS0.589479121302
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.3-3.430.41021080.33212171X-RAY DIFFRACTION78.94
3.43-3.590.35631300.29072310X-RAY DIFFRACTION85.31
3.59-3.780.35611230.27282438X-RAY DIFFRACTION89.83
3.78-4.010.3271280.25842580X-RAY DIFFRACTION93.48
4.01-4.320.28051390.20692589X-RAY DIFFRACTION95.22
4.32-4.760.22271460.1772679X-RAY DIFFRACTION97.68
4.76-5.440.22961520.1752683X-RAY DIFFRACTION98.2
5.44-6.850.26811470.19872680X-RAY DIFFRACTION97.72
6.85-36.030.21441310.16522836X-RAY DIFFRACTION98.41
Refinement TLS params.Method: refined / Origin x: -19.6604514506 Å / Origin y: 0.178849371771 Å / Origin z: 21.9337096463 Å
111213212223313233
T0.845175620655 Å2-0.0571578143079 Å20.086356319193 Å2-0.708250823662 Å2-0.100399545467 Å2--0.768454304296 Å2
L3.40242535884 °20.173668083221 °20.107102262463 °2-0.0273976136342 °2-0.0720926814997 °2---0.169546173365 °2
S-0.0476565857015 Å °-0.305726805973 Å °0.34643502309 Å °0.0546498771118 Å °0.0258011129776 Å °-0.0930565407309 Å °-0.0491008664155 Å °-9.06596338047E-5 Å °0.0187321215414 Å °
Refinement TLS groupSelection details: all

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