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- PDB-6wcz: CryoEM structure of full-length ZIKV NS5-hSTAT2 complex -

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Basic information

Entry
Database: PDB / ID: 6wcz
TitleCryoEM structure of full-length ZIKV NS5-hSTAT2 complex
Components
  • Non-structural protein 5
  • Signal transducer and activator of transcription 2
KeywordsIMMUNE SYSTEM / ZIKV NS5 / hSTAT2 / CryoEM
Function / homology
Function and homology information


ISGF3 complex / symbiont-mediated suppression of host interferon-mediated signaling pathway / negative regulation of type I interferon-mediated signaling pathway / Interleukin-20 family signaling / type I interferon-mediated signaling pathway / regulation of mitochondrial fission / regulation of protein phosphorylation / flavivirin / ubiquitin-like protein ligase binding / Regulation of IFNA/IFNB signaling ...ISGF3 complex / symbiont-mediated suppression of host interferon-mediated signaling pathway / negative regulation of type I interferon-mediated signaling pathway / Interleukin-20 family signaling / type I interferon-mediated signaling pathway / regulation of mitochondrial fission / regulation of protein phosphorylation / flavivirin / ubiquitin-like protein ligase binding / Regulation of IFNA/IFNB signaling / symbiont-mediated suppression of host JAK-STAT cascade via inhibition of host TYK2 activity / cell surface receptor signaling pathway via JAK-STAT / 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 / ribonucleoside triphosphate phosphatase activity / defense response / response to peptide hormone / Evasion by RSV of host interferon responses / 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 / protein-macromolecule adaptor activity / symbiont-mediated suppression of host toll-like receptor signaling pathway / clathrin-dependent endocytosis of virus by host cell / defense response to virus / molecular adaptor activity / mRNA (guanine-N7)-methyltransferase / methyltransferase cap1 / Potential therapeutics for SARS / methyltransferase cap1 activity / host cell cytoplasm / DNA-binding transcription factor activity, RNA polymerase II-specific / mRNA 5'-cap (guanine-N7-)-methyltransferase activity / RNA helicase activity / protein dimerization activity / host cell perinuclear region of cytoplasm / symbiont-mediated suppression of host innate immune response / 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 / viral envelope / lipid binding / regulation of transcription by RNA polymerase II / symbiont entry into host cell / chromatin / GTP binding / 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 / cytoplasm / cytosol
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 capsid protein C superfamily / Flavivirus non-structural protein NS2B / 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 / Vaccinia Virus protein VP39 / 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 / Rossmann fold / P-loop containing nucleoside triphosphate hydrolase / 2-Layer Sandwich / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Genome polyprotein / Signal transducer and activator of transcription 2 / Genome polyprotein
Similarity search - Component
Biological speciesHomo sapiens (human)
Zika virus
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4 Å
AuthorsBoxiao, W. / Stephanie, T. / Kang, Z. / Maria, T.S. / Jian, F. / Jiuwei, L. / Linfeng, G. / Wendan, R. / Yanxiang, C. / Ethan, C.V. ...Boxiao, W. / Stephanie, T. / Kang, Z. / Maria, T.S. / Jian, F. / Jiuwei, L. / Linfeng, G. / Wendan, R. / Yanxiang, C. / Ethan, C.V. / HeaJin, H. / Matthew, J.E. / Sean, E.O. / Adolfo, G.S. / Hong, Z. / Rong, H. / Jikui, S.
Funding support United States, 5items
OrganizationGrant numberCountry
National Institutes of Health/National Library of Medicine (NIH/NLM)1S10RR23057 United States
National Institutes of Health/National Library of Medicine (NIH/NLM)1S10OD018111 United States
National Institutes of Health/National Library of Medicine (NIH/NLM)1R35GM119721 United States
National Science Foundation (NSF, United States)DBI-1338135 United States
National Institutes of Health/National Library of Medicine (NIH/NLM)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
DepositionMar 31, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 8, 2020Provider: repository / Type: Initial release
Revision 1.1Oct 14, 2020Group: Database references / Category: citation
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Aug 25, 2021Group: Database references / Category: citation / citation_author / database_2
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.name / _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.3May 29, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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Assembly

Deposited unit
A: Signal transducer and activator of transcription 2
B: Non-structural protein 5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)201,2754
Polymers201,1442
Non-polymers1312
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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


Mass: 98025.031 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-Gold(DE3)pLysS AG' (bacteria)
References: UniProt: P52630
#2: Protein Non-structural protein 5


Mass: 103118.703 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Zika virus / Gene: GP1, A2G93_72125gpGP1, A2G93_72126gpGP1
Production host: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
References: UniProt: A0A2R4LVT4, UniProt: Q32ZE1*PLUS
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
Has ligand of interestN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

Component
IDNameTypeEntity IDParent-IDSource
1full-length ZIKV NS5-hSTAT2 complexCOMPLEX#1-#20MULTIPLE SOURCES
2hSTAT2COMPLEX#11RECOMBINANT
3ZIKV NS5COMPLEX#21RECOMBINANT
Molecular weightValue: 141 kDa/nm / Experimental value: YES
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
12Homo sapiens (human)9606
23Zika virus64320
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
12Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)866768
23Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)866768
Buffer solutionpH: 7.5 / Details: 25 mM Tris-HCl, pH 7.5, 175 mM NaCl, 5 mM DTT
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Cs: 2.7 mm
Image recordingElectron dose: 48 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

EM software
IDNameVersionCategory
1Gautomatch0.53particle selection
4CTFFIND4CTF correction
7UCSF Chimeramodel fitting
9RELION2initial Euler assignment
11RELION2classification
12RELION23D reconstruction
13PHENIXmodel refinement
14Cootmodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 118760 / Symmetry type: POINT

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