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8T12

Cryo-EM structure of DENV2 NS5 in complex with human STAT2 with the N-terminal domain of STAT2 ordered.

Summary for 8T12
Entry DOI10.2210/pdb8t12/pdb
EMDB information40952
DescriptorSignal transducer and activator of transcription 2, Non-structural protein 5, ZINC ION (3 entities in total)
Functional Keywordscomplex, immune system-viral protein complex, immune system/viral protein
Biological sourceHomo sapiens (Human)
More
Total number of polymer chains2
Total formula weight201420.51
Authors
Biswal, M.,Lu, J.,Song, J. (deposition date: 2023-06-01, release date: 2024-01-17, Last modification date: 2024-07-31)
Primary citationBiswal, M.,Yao, W.,Lu, J.,Chen, J.,Morrison, J.,Hai, R.,Song, J.
A conformational selection mechanism of flavivirus NS5 for species-specific STAT2 inhibition.
Commun Biol, 7:76-76, 2024
Cited by
PubMed 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 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.
PubMed: 38195857
DOI: 10.1038/s42003-024-05768-8
PDB entries with the same primary citation
Experimental method
ELECTRON MICROSCOPY (3.34 Å)
Structure validation

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