6ux2

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Crystal structure of ZIKV RdRp in complex with STAT2

Structural highlights

6ux2 is a 2 chain structure with sequence from Homo sapiens and Zika virus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 3.01Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

STAT2_HUMAN Signal transducer and activator of transcription that mediates signaling by type I IFNs (IFN-alpha and IFN-beta). Following type I IFN binding to cell surface receptors, Jak kinases (TYK2 and JAK1) are activated, leading to tyrosine phosphorylation of STAT1 and STAT2. The phosphorylated STATs dimerize, associate with IRF9/ISGF3G to form a complex termed ISGF3 transcription factor, that enters the nucleus. ISGF3 binds to the IFN stimulated response element (ISRE) to activate the transcription of interferon stimulated genes, which drive the cell in an antiviral state.^[1]

Publication Abstract from PubMed

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.

Structural basis for STAT2 suppression by flavivirus NS5.,Wang B, Thurmond S, Zhou K, Sanchez-Aparicio MT, Fang J, Lu J, Gao L, Ren W, Cui Y, Veit EC, Hong H, Evans MJ, O'Leary SE, Garcia-Sastre A, Zhou ZH, Hai R, Song J Nat Struct Mol Biol. 2020 Aug 10. pii: 10.1038/s41594-020-0472-y. doi:, 10.1038/s41594-020-0472-y. PMID:32778820^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Bluyssen HA, Levy DE. Stat2 is a transcriptional activator that requires sequence-specific contacts provided by stat1 and p48 for stable interaction with DNA. J Biol Chem. 1997 Feb 14;272(7):4600-5. PMID:9020188
↑ Wang B, Thurmond S, Zhou K, Sanchez-Aparicio MT, Fang J, Lu J, Gao L, Ren W, Cui Y, Veit EC, Hong H, Evans MJ, O'Leary SE, Garcia-Sastre A, Zhou ZH, Hai R, Song J. Structural basis for STAT2 suppression by flavivirus NS5. Nat Struct Mol Biol. 2020 Aug 10. pii: 10.1038/s41594-020-0472-y. doi:, 10.1038/s41594-020-0472-y. PMID:32778820 doi:http://dx.doi.org/10.1038/s41594-020-0472-y