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- PDB-8t12: Cryo-EM structure of DENV2 NS5 in complex with human STAT2 with t... -
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Basic information
Entry | Database: PDB / ID: 8t12 | ||||||
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Title | Cryo-EM structure of DENV2 NS5 in complex with human STAT2 with the N-terminal domain of STAT2 ordered. | ||||||
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![]() | IMMUNE SYSTEM/VIRAL PROTEIN / complex / IMMUNE SYSTEM-VIRAL PROTEIN complex | ||||||
Function / homology | ![]() ISGF3 complex / negative regulation of type I interferon-mediated signaling pathway / Interleukin-20 family signaling / type I interferon-mediated signaling pathway / regulation of mitochondrial fission / ubiquitin-like protein ligase binding / symbiont-mediated suppression of host JAK-STAT cascade via inhibition of host TYK2 activity / cell surface receptor signaling pathway via JAK-STAT / host cell mitochondrion / Regulation of IFNA/IFNB signaling ...ISGF3 complex / negative regulation of type I interferon-mediated signaling pathway / Interleukin-20 family signaling / type I interferon-mediated signaling pathway / regulation of mitochondrial fission / ubiquitin-like protein ligase binding / symbiont-mediated suppression of host JAK-STAT cascade via inhibition of host TYK2 activity / cell surface receptor signaling pathway via JAK-STAT / host cell mitochondrion / Regulation of IFNA/IFNB signaling / symbiont-mediated suppression of host JAK-STAT cascade via inhibition of STAT2 activity / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of MAVS activity / ribonucleoside triphosphate phosphatase activity / regulation of protein phosphorylation / Evasion by RSV of host interferon responses / RNA polymerase II transcription regulator complex / response to peptide hormone / defense response / viral capsid / double-stranded RNA binding / Interferon alpha/beta signaling / protein complex oligomerization / monoatomic ion channel activity / regulation of cell population proliferation / Potential therapeutics for SARS / clathrin-dependent endocytosis of virus by host cell / defense response to virus / mRNA (nucleoside-2'-O-)-methyltransferase activity / mRNA 5'-cap (guanine-N7-)-methyltransferase activity / RNA helicase activity / DNA-binding transcription factor activity, RNA polymerase II-specific / host cell endoplasmic reticulum membrane / protein dimerization activity / symbiont-mediated suppression of host type I interferon-mediated signaling pathway / induction by virus of host autophagy / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-binding transcription factor activity / serine-type endopeptidase activity / viral RNA genome replication / virus-mediated perturbation of host defense response / RNA-dependent RNA polymerase activity / fusion of virus membrane with host endosome membrane / viral envelope / host cell nucleus / regulation of transcription by RNA polymerase II / chromatin / virion attachment to host cell / SARS-CoV-2 activates/modulates innate and adaptive immune responses / structural molecule activity / virion membrane / positive regulation of transcription by RNA polymerase II / proteolysis / extracellular region / nucleoplasm / ATP binding / identical protein binding / membrane / nucleus / metal ion binding / plasma membrane / cytoplasm / cytosol Similarity search - Function | ||||||
Biological species | ![]() ![]() | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.34 Å | ||||||
![]() | Biswal, M. / Lu, J. / Song, J. | ||||||
Funding support | ![]()
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![]() | ![]() Title: A conformational selection mechanism of flavivirus NS5 for species-specific STAT2 inhibition. Authors: Mahamaya Biswal / Wangyuan Yao / Jiuwei Lu / Jianbin Chen / Juliet Morrison / Rong Hai / Jikui Song / ![]() Abstract: Flaviviruses, including Zika virus (ZIKV) and Dengue virus (DENV), rely on their non-structural protein 5 (NS5) for both replication of viral genome and suppression of host IFN signaling. DENV and ...Flaviviruses, including Zika virus (ZIKV) and Dengue virus (DENV), rely on their non-structural protein 5 (NS5) for both replication of viral genome and suppression of host IFN signaling. DENV and ZIKV NS5s were shown to facilitate proteosome-mediated protein degradation of human STAT2 (hSTAT2). However, how flavivirus NS5s have evolved for species-specific IFN-suppression remains unclear. Here we report structure-function characterization of the DENV serotype 2 (DENV2) NS5-hSTAT2 complex. The MTase and RdRP domains of DENV2 NS5 form an extended conformation to interact with the coiled-coil and N-terminal domains of hSTAT2, thereby promoting hSTAT2 degradation in cells. Disruption of the extended conformation of DENV2/ZIKV NS5, but not the alternative compact state, impaired their hSTAT2 binding. Our comparative structural analysis of flavivirus NS5s further reveals a conserved protein-interaction platform with subtle amino-acid variations likely underpinning diverse IFN-suppression mechanisms. Together, this study uncovers a conformational selection mechanism underlying species-specific hSTAT2 inhibition by flavivirus NS5. | ||||||
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Structure visualization
Structure viewer | Molecule: ![]() ![]() |
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Downloads & links
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PDBx/mmCIF format | ![]() | 284.5 KB | Display | ![]() |
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PDB format | ![]() | 222.3 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
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-Validation report
Summary document | ![]() | 1.2 MB | Display | ![]() |
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Full document | ![]() | 1.2 MB | Display | |
Data in XML | ![]() | 49.3 KB | Display | |
Data in CIF | ![]() | 72.2 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 40952MC ![]() 8t13C M: map data used to model this data C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Assembly
Deposited unit | ![]()
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Components
#1: Protein | Mass: 98025.031 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() | ||
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#2: Protein | Mass: 103264.656 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() | ||
#3: Chemical | Has ligand of interest | Y | |
-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
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Sample preparation
Component | Name: complex of DENV2 NS5 and huamn STAT2 / Type: COMPLEX / Entity ID: #1-#2 / Source: MULTIPLE SOURCES | ||||||||||||
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Source (natural) |
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Source (recombinant) | Organism: ![]() ![]() | ||||||||||||
Buffer solution | pH: 7.5 | ||||||||||||
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES | ||||||||||||
Vitrification | Cryogen name: ETHANE |
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Electron microscopy imaging
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: ![]() |
Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 1000 nm |
Image recording | Electron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) |
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Processing
CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION |
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3D reconstruction | Resolution: 3.34 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 99938 / Symmetry type: POINT |