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- PDB-6ux2: Crystal structure of ZIKV RdRp in complex with STAT2 -

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Basic information

Entry
Database: PDB / ID: 6ux2
TitleCrystal structure of ZIKV RdRp in complex with STAT2
Components
  • Nonstructural Protein 5
  • Signal transducer and activator of transcription 2
KeywordsDNA BINDING PROTEIN/VIRAL PROTEIN / host-pathogen interaction / VIRAL PROTEIN / DNA BINDING PROTEIN-VIRAL PROTEIN complex
Function / homology
Function and homology information


ISGF3 complex / symbiont-mediated suppression of host interferon-mediated signaling pathway / Interleukin-20 family signaling / negative regulation of type I interferon-mediated signaling pathway / type I interferon-mediated signaling pathway / regulation of mitochondrial fission / ubiquitin-like protein ligase binding / Regulation of IFNA/IFNB signaling / regulation of protein phosphorylation / flavivirin ...ISGF3 complex / symbiont-mediated suppression of host interferon-mediated signaling pathway / Interleukin-20 family signaling / negative regulation of type I interferon-mediated signaling pathway / type I interferon-mediated signaling pathway / regulation of mitochondrial fission / ubiquitin-like protein ligase binding / Regulation of IFNA/IFNB signaling / regulation of protein phosphorylation / flavivirin / cell surface receptor signaling pathway via JAK-STAT / symbiont-mediated suppression of host JAK-STAT cascade via inhibition of host TYK2 activity / symbiont-mediated suppression of host JAK-STAT cascade via inhibition of STAT2 activity / symbiont-mediated suppression of host JAK-STAT cascade via inhibition of STAT1 activity / defense response / Evasion by RSV of host interferon responses / response to peptide hormone / RNA polymerase II transcription regulator complex / Interferon alpha/beta signaling / viral capsid / double-stranded RNA binding / regulation of cell population proliferation / nucleoside-triphosphate phosphatase / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of TBK1 activity / symbiont-mediated suppression of host toll-like receptor signaling pathway / protein-macromolecule adaptor activity / mRNA (guanine-N7)-methyltransferase / methyltransferase cap1 / defense response to virus / clathrin-dependent endocytosis of virus by host cell / Potential therapeutics for SARS / methyltransferase cap1 activity / mRNA 5'-cap (guanine-N7-)-methyltransferase activity / host cell cytoplasm / DNA-binding transcription factor activity, RNA polymerase II-specific / RNA helicase activity / protein dimerization activity / host cell perinuclear region of cytoplasm / host cell endoplasmic reticulum membrane / RNA helicase / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-binding transcription factor activity / symbiont-mediated activation of host autophagy / RNA-directed RNA polymerase / serine-type endopeptidase activity / viral RNA genome replication / RNA-directed RNA polymerase activity / fusion of virus membrane with host endosome membrane / lipid binding / viral envelope / regulation of transcription by RNA polymerase II / GTP binding / chromatin / virion attachment to host cell / host cell nucleus / SARS-CoV-2 activates/modulates innate and adaptive immune responses / virion membrane / structural molecule activity / positive regulation of transcription by RNA polymerase II / ATP hydrolysis activity / proteolysis / extracellular region / nucleoplasm / ATP binding / metal ion binding / identical protein binding / nucleus / membrane / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Signal transducer and activation of transcription 2, C-terminal / STAT2, SH2 domain / Signal transducer and activator of transcription 2 C terminal / Flavivirus RNA-directed RNA polymerase, thumb domain / STAT transcription factor, DNA-binding, N-terminal / STAT transcription factor, protein interaction / STAT transcription factor, all-alpha domain / STAT transcription factor, DNA-binding / : / STAT transcription factor, coiled-coil domain ...Signal transducer and activation of transcription 2, C-terminal / STAT2, SH2 domain / Signal transducer and activator of transcription 2 C terminal / Flavivirus RNA-directed RNA polymerase, thumb domain / STAT transcription factor, DNA-binding, N-terminal / STAT transcription factor, protein interaction / STAT transcription factor, all-alpha domain / STAT transcription factor, DNA-binding / : / STAT transcription factor, coiled-coil domain / STAT protein, DNA binding domain / STAT protein, protein interaction domain / Signal transducer and activator of transcription, linker domain / STAT protein, protein interaction domain / STAT transcription factor, N-terminal domain superfamily / Transcription factor STAT / STAT transcription factor, coiled coil / p53-like transcription factor, DNA-binding / Flavivirus non-structural protein NS2B / Flavivirus capsid protein C superfamily / Genome polyprotein, Flavivirus / : / Flavivirus non-structural protein NS4A / Flavivirus non-structural protein NS2B / Flavivirus non-structural protein NS4B / mRNA cap 0/1 methyltransferase / Flavivirus non-structural protein NS4B / Flavivirus non-structural protein NS4A / Flavivirus NS2B domain profile. / mRNA cap 0 and cap 1 methyltransferase (EC 2.1.1.56 and EC 2.1.1.57) domain profile. / Flavivirus non-structural protein NS2A / Flavivirus non-structural protein NS2A / Flavivirus NS3, petidase S7 / Peptidase S7, Flavivirus NS3 serine protease / Flavivirus NS3 protease (NS3pro) domain profile. / RNA-directed RNA polymerase, thumb domain, Flavivirus / Flavivirus RNA-directed RNA polymerase, thumb domain / RNA-directed RNA polymerase, flavivirus / Flavivirus RNA-directed RNA polymerase, fingers and palm domains / Flavivirus capsid protein C / Flavivirus capsid protein C / Flavivirus non-structural Protein NS1 / Flavivirus non-structural protein NS1 / Envelope glycoprotein M, flavivirus / Envelope glycoprotein M superfamily, flavivirus / Flavivirus envelope glycoprotein M / Flavivirus polyprotein propeptide / Flavivirus polyprotein propeptide superfamily / Flavivirus polyprotein propeptide / Flavivirus envelope glycoprotein E, stem/anchor domain / : / Flavivirus NS3 helicase, C-terminal helical domain / Flavivirus envelope glycoprotein E, Stem/Anchor domain / Flavivirus envelope glycoprotein E, Stem/Anchor domain superfamily / Flavivirus glycoprotein E, immunoglobulin-like domain / Flavivirus glycoprotein, immunoglobulin-like domain / Flavivirus glycoprotein central and dimerisation domain / Flavivirus glycoprotein, central and dimerisation domains / Flaviviral glycoprotein E, central domain, subdomain 1 / Flaviviral glycoprotein E, central domain, subdomain 2 / Ribosomal RNA methyltransferase, FtsJ domain / FtsJ-like methyltransferase / Flavivirus/Alphavirus glycoprotein, immunoglobulin-like domain superfamily / Flavivirus glycoprotein, central and dimerisation domain superfamily / Flaviviral glycoprotein E, dimerisation domain / DEAD box, Flavivirus / Flavivirus DEAD domain / SH2 domain / Src homology 2 (SH2) domain profile. / Src homology 2 domains / SH2 domain / SH2 domain superfamily / helicase superfamily c-terminal domain / Immunoglobulin E-set / Superfamilies 1 and 2 helicase C-terminal domain profile. / Superfamilies 1 and 2 helicase ATP-binding type-1 domain profile. / DEAD-like helicases superfamily / Helicase, C-terminal / Helicase superfamily 1/2, ATP-binding domain / Alpha-Beta Plaits / RNA-directed RNA polymerase, catalytic domain / RdRp of positive ssRNA viruses catalytic domain profile. / S-adenosyl-L-methionine-dependent methyltransferase superfamily / Peptidase S1, PA clan / DNA/RNA polymerase superfamily / P-loop containing nucleoside triphosphate hydrolase / 2-Layer Sandwich / Alpha Beta
Similarity search - Domain/homology
Signal transducer and activator of transcription 2 / Genome polyprotein
Similarity search - Component
Biological speciesHomo sapiens (human)
Zika virus
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.01 Å
AuthorsWang, B. / Song, J.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Human Genome Research Institute (NIH/NHGRI)1R21AI147057 United States
CitationJournal: Nat Struct Mol Biol / Year: 2020
Title: Structural basis for STAT2 suppression by flavivirus NS5.
Authors: Boxiao Wang / Stephanie Thurmond / Kang Zhou / Maria T Sánchez-Aparicio / Jian Fang / Jiuwei Lu / Linfeng Gao / Wendan Ren / Yanxiang Cui / Ethan C Veit / HeaJin Hong / Matthew J Evans / ...Authors: Boxiao Wang / Stephanie Thurmond / Kang Zhou / Maria T Sánchez-Aparicio / Jian Fang / Jiuwei Lu / Linfeng Gao / Wendan Ren / Yanxiang Cui / Ethan C Veit / HeaJin Hong / Matthew J Evans / Seán E O'Leary / Adolfo García-Sastre / Z Hong Zhou / Rong Hai / Jikui Song /
Abstract: Suppressing cellular signal transducers of transcription 2 (STAT2) is a common strategy that viruses use to establish infections, yet the detailed mechanism remains elusive, owing to a lack of ...Suppressing cellular signal transducers of transcription 2 (STAT2) is a common strategy that viruses use to establish infections, yet the detailed mechanism remains elusive, owing to a lack of structural information about the viral-cellular complex involved. Here, we report the cryo-EM and crystal structures of human STAT2 (hSTAT2) in complex with the non-structural protein 5 (NS5) of Zika virus (ZIKV) and dengue virus (DENV), revealing two-pronged interactions between NS5 and hSTAT2. First, the NS5 methyltransferase and RNA-dependent RNA polymerase (RdRP) domains form a conserved interdomain cleft harboring the coiled-coil domain of hSTAT2, thus preventing association of hSTAT2 with interferon regulatory factor 9. Second, the NS5 RdRP domain also binds the amino-terminal domain of hSTAT2. Disruption of these ZIKV NS5-hSTAT2 interactions compromised NS5-mediated hSTAT2 degradation and interferon suppression, and viral infection under interferon-competent conditions. Taken together, these results clarify the mechanism underlying the functional antagonism of STAT2 by both ZIKV and DENV.
History
DepositionNov 6, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 8, 2020Provider: repository / Type: Initial release
Revision 1.1Aug 12, 2020Group: Database references / Category: citation / citation_author / Item: _citation.pdbx_database_id_DOI
Revision 1.2Aug 26, 2020Group: Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name
Revision 1.3Oct 21, 2020Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.4Oct 11, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Signal transducer and activator of transcription 2
B: Nonstructural Protein 5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)156,5018
Polymers155,9862
Non-polymers5156
Water1,49583
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: microscopy
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3280 Å2
ΔGint-106 kcal/mol
Surface area54990 Å2
MethodPISA
Unit cell
Length a, b, c (Å)85.113, 124.700, 84.783
Angle α, β, γ (deg.)90.000, 109.392, 90.000
Int Tables number4
Space group name H-MP1211
Space group name HallP2yb
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z

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Components

#1: Protein Signal transducer and activator of transcription 2 / p113


Mass: 82825.812 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: STAT2 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P52630
#2: Protein Nonstructural Protein 5


Mass: 73160.305 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Zika virus / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: Q32ZE1, flavivirin, nucleoside-triphosphate phosphatase, RNA helicase, mRNA (guanine-N7)-methyltransferase, methyltransferase cap1, RNA-directed RNA polymerase
#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 83 / Source method: isolated from a natural source / Formula: H2O
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: 2.98 Å3/Da / Density % sol: 58.79 %
Crystal growTemperature: 298.15 K / Method: vapor diffusion, hanging drop / pH: 8.5
Details: 0.2 M ammonium sulfate, 11% PEG 8000 and 0.1 M Tris-HCl, pH 8.5

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Data collection

DiffractionMean temperature: 277 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.1 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jan 30, 2018
RadiationMonochromator: singlewavelength / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3.008→49.24 Å / Num. obs: 32545 / % possible obs: 97.86 % / Redundancy: 5.9 % / Biso Wilson estimate: 63.53 Å2 / CC1/2: 0.996 / Net I/σ(I): 9.52
Reflection shellResolution: 3.008→3.115 Å / Num. unique obs: 2737 / CC1/2: 0.82

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Processing

Software
NameVersionClassification
PHENIX1.13_2998refinement
HKL-2000data reduction
HKL-2000data scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1YVL 5TMH

1yvl

5tmh


Resolution: 3.01→49.24 Å / SU ML: 0.4314 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 32.1021 / Stereochemistry target values: GeoStd + Monomer Library
RfactorNum. reflection% reflection
Rfree0.2635 2000 6.15 %
Rwork0.2418 30545 -
obs0.2432 32545 97.74 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 69.75 Å2
Refinement stepCycle: LAST / Resolution: 3.01→49.24 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9260 0 22 83 9365
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00539492
X-RAY DIFFRACTIONf_angle_d0.656312927
X-RAY DIFFRACTIONf_chiral_restr0.04721439
X-RAY DIFFRACTIONf_plane_restr0.00481666
X-RAY DIFFRACTIONf_dihedral_angle_d19.56223301
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.01-3.080.36081100.36341685X-RAY DIFFRACTION75.8
3.08-3.170.36441460.33222164X-RAY DIFFRACTION97.51
3.17-3.260.38431440.31982217X-RAY DIFFRACTION99.12
3.26-3.360.3811410.30432178X-RAY DIFFRACTION99.06
3.36-3.480.33661450.28352201X-RAY DIFFRACTION99.32
3.48-3.620.29911470.26012216X-RAY DIFFRACTION99.7
3.62-3.790.28731500.25092216X-RAY DIFFRACTION99.5
3.79-3.990.24121440.23482228X-RAY DIFFRACTION99.75
3.99-4.240.25611420.22172227X-RAY DIFFRACTION99.66
4.24-4.560.22281430.21022225X-RAY DIFFRACTION99.75
4.56-5.020.21151460.21062240X-RAY DIFFRACTION99.75
5.02-5.750.25351460.22742223X-RAY DIFFRACTION99.83
5.75-7.240.25211440.24492246X-RAY DIFFRACTION99.87
7.24-49.240.20771520.20392279X-RAY DIFFRACTION99.63

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