The structure of Zika virus NS5 reveals a conserved domain conformation

Abstract

The recent outbreak of Zika virus (ZIKV) has imposed a serious threat to public health. Here we report the crystal structure of the ZIKV NS5 protein in complex with S-adenosyl-L-homocysteine, in which the tandem methyltransferase (MTase) and RNA-dependent RNA polymerase (RdRp) domains stack into one of the two alternative conformations of flavivirus NS5 proteins. The activity of this NS5 protein is verified through a de novo RdRp assay on a subgenomic ZIKV RNA template. Importantly, our structural analysis leads to the identification of a potential drug-binding site of ZIKV NS5, which might facilitate the development of novel antivirals for ZIKV.

Probing the Pharmacological Parameters, Molecular Docking and Quantum Computations of Plant Derived Compounds Exhibiting Strong Inhibitory Potential Against NS5 from Zika Virus

“…Tertiary structure of ZIKV-NS5 reveals an N-terminal MTase domain, situated at the top of Cterminal RdRp domain. A Rossmann fold dominates the MTase domain with a seven stranded β-sheet, between two α-helices 21 . To find the potential inhibitors, a total of 2035 phytochemicals were analysed for in this study for their inhibitory potential against ZIKV-NS5.…”

The A–Z of Zika drug discovery

“…The study suggests that: (i) NS5 recruits SIAH2 for the ubiquitination-dependent degradation of STAT2; and (ii) the NS5 amino acid residues involved in interaction with SIAH2 and/or STAT2 were found to be conserved across related flaviviruses [42]. Another structural study of ZIKV NS5 indicated that the smallmolecule inhibitor-binding site of DENV3 NS5 is structurally conserved in ZIKV NS5, indicating a potential mechanism for functional inhibition of ZIKV NS5 [43]. In principle, small molecules interfering with the function of any ZIKV viral proteins have potential in restricting virus replication and preventing the progress of ZIKV-infection-related pathogenesis and diseases.…”

Broad-spectrum agents for flaviviral infections: dengue, Zika and beyond

“…The catalytic site is positioned at the intersection of two tunnels; one provides access to the active site for the single-stranded RNA template and the second tunnel allows entry of NTPs at one end and exit of the nascent double-stranded RNA at the other end 84,85 . Recently, the crystal structures of the ZIKV full-length NS5 protein 86,87 and RdRp 88 were reported.…”