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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.