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TitleA conformational selection mechanism of flavivirus NS5 for species-specific STAT2 inhibition.
Journal, issue, pagesCommun Biol, Vol. 7, Issue 1, Page 76, Year 2024
Publish dateJan 10, 2024
AuthorsMahamaya Biswal / Wangyuan Yao / Jiuwei Lu / Jianbin Chen / Juliet Morrison / Rong Hai / Jikui Song /
PubMed AbstractFlaviviruses, 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.
External linksCommun Biol / PubMed:38195857 / PubMed Central
MethodsEM (single particle)
Resolution3.34 - 3.45 Å
Structure data

EMDB-40952, PDB-8t12:
Cryo-EM structure of DENV2 NS5 in complex with human STAT2 with the N-terminal domain of STAT2 ordered.
Method: EM (single particle) / Resolution: 3.34 Å

EMDB-40953, PDB-8t13:
Cryo-EM structure of DENV2 NS5 in complex with human STAT2 with the N-terminal domain of STAT2 disordered
Method: EM (single particle) / Resolution: 3.45 Å

Chemicals

ChemComp-ZN:
Unknown entry

Source
  • homo sapiens (human)
  • dengue virus type 2
KeywordsIMMUNE SYSTEM/VIRAL PROTEIN / complex / IMMUNE SYSTEM-VIRAL PROTEIN complex

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