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- PDB-8wsn: Crystal structure of SFTSV Gn and antibody SF1 -

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Basic information

Entry
Database: PDB / ID: 8wsn
TitleCrystal structure of SFTSV Gn and antibody SF1
Components
  • Ab1-H
  • Ab1-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 / symbiont entry into host cell / fusion of virus membrane with host endosome membrane / 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 JS4
Homo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.8 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Gn
B: Ab1-H
C: Ab1-L
D: Gn
E: Ab1-H
F: Ab1-L
hetero molecules


Theoretical massNumber of molelcules
Total (without water)170,75312
Polymers169,0206
Non-polymers1,7346
Water2,648147
1
A: Gn
B: Ab1-H
C: Ab1-L
hetero molecules


Theoretical massNumber of molelcules
Total (without water)85,3776
Polymers84,5103
Non-polymers8673
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
D: Gn
E: Ab1-H
F: Ab1-L
hetero molecules


Theoretical massNumber of molelcules
Total (without water)85,3776
Polymers84,5103
Non-polymers8673
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)227.057, 97.249, 133.092
Angle α, β, γ (deg.)90.000, 124.624, 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_1(chain "A" and (resid 22 through 33 or (resid 34...
d_2ens_1(chain "D" and (resid 22 through 266 or (resid 267...
d_1ens_2(chain "B" and (resid 2 through 135 or resid 144 through 222 or resid 401 through 402))
d_2ens_2(chain "E" and resid 2 through 402)
d_1ens_3(chain "C" and resid 2 through 212)
d_2ens_3(chain "F" and (resid 2 through 96 or (resid 97...

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_1GLYGLYHISHISAA22 - 2943 - 275
d_12ens_1LYSLYSVALVALAA302 - 339283 - 320
d_13ens_1NAGNAGNAGNAGAI400
d_14ens_1NAGNAGNAGNAGAJ401
d_21ens_1GLYGLYHISHISDD22 - 2943 - 275
d_22ens_1LYSLYSVALVALDD302 - 339283 - 320
d_23ens_1NAGNAGNAGNAGDK400
d_24ens_1NAGNAGNAGNAGDL401
d_11ens_2VALVALPROPROBB2 - 1352 - 135
d_12ens_2THRTHRPROPROBB144 - 222144 - 222
d_13ens_2NAGNAGNAGNAGGG1
d_14ens_2NAGNAGNAGNAGGG2
d_21ens_2VALVALPROPROEE2 - 2222 - 222
d_22ens_2NAGNAGNAGNAGHH1
d_23ens_2NAGNAGNAGNAGHH2
d_11ens_3ILEILEARGARGCC2 - 2122 - 212
d_21ens_3ILEILEARGARGFF2 - 2122 - 212

NCS ensembles :
ID
ens_1
ens_2
ens_3

NCS oper:
IDCodeMatrixVector
1given(-0.999732568523, -0.0160353319572, -0.0166631198297), (0.0163520493439, -0.999684843727, -0.019047931765), (-0.0163524284341, -0.0193153139061, 0.999679707073)40.6907309612, 122.574886654, 2.27737451564
2given(-0.99988455944, -0.00273820741656, 0.0149455683306), (0.00274212033042, -0.999996211262, 0.000241324801259), (0.0149448509084, 0.000282279489357, 0.999888279634)37.1983062882, 121.791598155, -0.175427272336
3given(-0.999843051499, -0.00306289131344, 0.0174496723925), (0.00312306235537, -0.99998926795, 0.0034220558263), (0.0174390037367, 0.00347601515472, 0.999841886734)37.1216309481, 121.488058325, -0.339157202669

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Components

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Protein , 2 types, 4 molecules ADBE

#1: Protein Gn


Mass: 36195.906 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) SFTS virus JS4 / Production host: Homo sapiens (human) / References: UniProt: F1BWV6
#2: Protein Ab1-H


Mass: 24761.818 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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Antibody / Non-polymers , 2 types, 149 molecules CF

#3: Antibody Ab1-L


Mass: 23552.160 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 147 / Source method: isolated from a natural source / Formula: H2O

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Sugars , 2 types, 6 molecules

#4: 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-ROHGlycam 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
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}LINUCSPDB-CARE
#5: 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.: 4 / 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 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: 65.61 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: 0.2 M Potassium bromide, 0.2 M Potassium thiocyanate, 0.1 M Sodium cacodylate, pH 6.5, 3 % w/v gamma-PGA (Na+ form, LM), 30 % v/v PEG 400

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL19U1 / Wavelength: 1.00389 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: 1.00389 Å / Relative weight: 1
ReflectionResolution: 2.8→50 Å / Num. obs: 58608 / % possible obs: 99.9 % / Redundancy: 5.2 % / Biso Wilson estimate: 60.82 Å2 / CC1/2: 0.981 / Rpim(I) all: 0.08 / Net I/σ(I): 9.9
Reflection shellResolution: 2.8→2.9 Å / Redundancy: 5 % / Num. unique obs: 5794 / CC1/2: 0.583 / Rpim(I) all: 0.516 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX1.19.2_4158refinement
PHENIX1.19.2_4158refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.8→46.71 Å / SU ML: 0.4298 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 30.2204
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2908 2942 5.02 %
Rwork0.2396 55638 -
obs0.2421 58580 99.42 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 58.95 Å2
Refinement stepCycle: LAST / Resolution: 2.8→46.71 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms11384 0 112 147 11643
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.010311794
X-RAY DIFFRACTIONf_angle_d1.232516002
X-RAY DIFFRACTIONf_chiral_restr0.06061746
X-RAY DIFFRACTIONf_plane_restr0.01382040
X-RAY DIFFRACTIONf_dihedral_angle_d7.1441639
Refine LS restraints NCS
Ens-IDDom-IDAsym-IDAuth asym-IDRefine-IDTypeRms dev position (Å)
ens_1d_2AAX-RAY DIFFRACTIONTorsion NCS0.865454616241
ens_2d_2BBX-RAY DIFFRACTIONTorsion NCS0.832763649556
ens_3d_2CCX-RAY DIFFRACTIONTorsion NCS0.774634169939
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.8-2.850.37811100.29762395X-RAY DIFFRACTION89.91
2.85-2.890.37891290.30082626X-RAY DIFFRACTION100
2.89-2.950.33241350.2882687X-RAY DIFFRACTION100
2.95-30.33291330.27982639X-RAY DIFFRACTION99.96
3-3.070.32251460.26662638X-RAY DIFFRACTION99.96
3.07-3.130.34281270.26252673X-RAY DIFFRACTION100
3.13-3.20.30681590.25872605X-RAY DIFFRACTION100
3.2-3.280.32931240.25192679X-RAY DIFFRACTION100
3.28-3.370.27061500.24332639X-RAY DIFFRACTION99.96
3.37-3.470.27881350.24012653X-RAY DIFFRACTION99.93
3.47-3.580.32461560.23772656X-RAY DIFFRACTION99.86
3.58-3.710.31161690.2372594X-RAY DIFFRACTION99.82
3.71-3.860.30471390.22512715X-RAY DIFFRACTION100
3.86-4.040.27661540.21842644X-RAY DIFFRACTION100
4.04-4.250.26041510.2042623X-RAY DIFFRACTION99.96
4.25-4.520.22341230.19062681X-RAY DIFFRACTION99.93
4.52-4.860.24951350.20152682X-RAY DIFFRACTION99.79
4.86-5.350.25771330.20822694X-RAY DIFFRACTION99.79
5.35-6.130.30261400.24312674X-RAY DIFFRACTION99.72
6.13-7.710.28911530.26792690X-RAY DIFFRACTION99.93
7.71-46.710.30641410.28492751X-RAY DIFFRACTION99.45
Refinement TLS params.Method: refined / Origin x: 19.3067984685 Å / Origin y: 60.854891101 Å / Origin z: 81.9453490509 Å
111213212223313233
T0.418925636301 Å2-0.027743060281 Å20.00727341259637 Å2-0.389290470802 Å20.00427776914934 Å2--0.322103495429 Å2
L0.372701302492 °2-0.291282932114 °20.05008564877 °2-0.63529071606 °20.0145981984178 °2--0.191927250848 °2
S0.0590168726646 Å °-0.0872362000869 Å °-0.00667167909096 Å °0.0319936890661 Å °-0.012088673917 Å °-0.000797293609451 Å °0.00842098785492 Å °-0.00165214640109 Å °-0.0445799336503 Å °
Refinement TLS groupSelection details: all

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