6UX2

Crystal structure of ZIKV RdRp in complex with STAT2

Summary for 6UX2

• Entry DOI: 10.2210/pdb6ux2/pdb
• Descriptor: Signal transducer and activator of transcription 2, Nonstructural Protein 5, SULFATE ION, ... (5 entities in total)
• Functional Keywords: host-pathogen interaction, viral protein, dna binding protein-viral protein complex, dna binding protein/viral protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 156501.19

Authors

Wang, B.,Song, J. (deposition date: 2019-11-06, release date: 2020-07-08, Last modification date: 2023-10-11)

Primary citation

Wang, B.,Thurmond, S.,Zhou, K.,Sanchez-Aparicio, M.T.,Fang, J.,Lu, J.,Gao, L.,Ren, W.,Cui, Y.,Veit, E.C.,Hong, H.,Evans, M.J.,O'Leary, S.E.,Garcia-Sastre, A.,Zhou, Z.H.,Hai, R.,Song, J.
Structural basis for STAT2 suppression by flavivirus NS5.
Nat.Struct.Mol.Biol., 27:875-885, 2020

PubMed Abstract: 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.

PubMed: 32778820
DOI: 10.1038/s41594-020-0472-y

Experimental method

X-RAY DIFFRACTION (3.01 Å)