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.
Highlights
The recent outbreak of Zika virus (ZIKV) has imposed a serious threat to public health
ZIKV belongs to the family of flavivirus that includes a variety of mosquito-borne human pathogens, such as dengue virus (DENV1–4), yellow fever virus, West Nile virus, Spondweni virus and Japanese encephalitis virus (JEV)[5]
NS5 is the largest NS protein, containing an N-terminal methyltransferase (MTase) domain responsible for viral RNA capping and a C-terminal RNA-dependent RNA polymerase (RdRp) domain for viral RNA synthesis, with evidence indicating that the MTase and RdRp domains cooperate in RNA synthesis initiation and elongation[7]
Summary
The recent outbreak of Zika virus (ZIKV) has imposed a serious threat to public health. 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. To illuminate the structure and mechanism of NS5 proteins, and, more importantly, to explore potential druggable sites for ZIKV, we determined the crystal structure of full-length ZIKV NS5 in complex with S-adenosyl-L-homocysteine (SAH), by-product of cofactor S-adenosyl-L-methionine at 3.3 Å resolution. We show that the structure of ZIKV NS5 provides a framework for future development of novel antivirals against ZIKV infection
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