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Title: Structure and function of the Zika virus full-length NS5 protein

Abstract

The recent outbreak of Zika virus (ZIKV) has infected over 1 million people in over 30 countries. ZIKV replicates its RNA genome using virally encoded replication proteins. Nonstructural protein 5 (NS5) contains a methyltransferase for RNA capping and a polymerase for viral RNA synthesis. Here we report the crystal structures of full-length NS5 and its polymerase domain at 3.0 Å resolution. The NS5 structure has striking similarities to the NS5 protein of the related Japanese encephalitis virus. The methyltransferase contains in-line pockets for substrate binding and the active site. Key residues in the polymerase are located in similar positions to those of the initiation complex for the hepatitis C virus polymerase. The polymerase conformation is affected by the methyltransferase, which enables a more efficiently elongation of RNA synthesis in vitro. Altogether, our results will contribute to future studies on ZIKV infection and the development of inhibitors of ZIKV replication.

Authors:
 [1];  [2];  [1];  [2];  [2];  [3];  [2];  [1]
  1. Texas A & M Univ., College Station, TX (United States)
  2. Indiana Univ., Bloomington, IN (United States)
  3. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Publication Date:
Research Org.:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
OSTI Identifier:
1409432
Grant/Contract Number:
AC02-05CH11231
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Nature Communications
Additional Journal Information:
Journal Volume: 8; Journal ID: ISSN 2041-1723
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES

Citation Formats

Zhao, Baoyu, Yi, Guanghui, Du, Fenglei, Chuang, Yin -Chih, Vaughan, Robert C., Sankaran, Banumathi, Kao, C. Cheng, and Li, Pingwei. Structure and function of the Zika virus full-length NS5 protein. United States: N. p., 2017. Web. doi:10.1038/ncomms14762.
Zhao, Baoyu, Yi, Guanghui, Du, Fenglei, Chuang, Yin -Chih, Vaughan, Robert C., Sankaran, Banumathi, Kao, C. Cheng, & Li, Pingwei. Structure and function of the Zika virus full-length NS5 protein. United States. doi:10.1038/ncomms14762.
Zhao, Baoyu, Yi, Guanghui, Du, Fenglei, Chuang, Yin -Chih, Vaughan, Robert C., Sankaran, Banumathi, Kao, C. Cheng, and Li, Pingwei. Mon . "Structure and function of the Zika virus full-length NS5 protein". United States. doi:10.1038/ncomms14762. https://www.osti.gov/servlets/purl/1409432.
@article{osti_1409432,
title = {Structure and function of the Zika virus full-length NS5 protein},
author = {Zhao, Baoyu and Yi, Guanghui and Du, Fenglei and Chuang, Yin -Chih and Vaughan, Robert C. and Sankaran, Banumathi and Kao, C. Cheng and Li, Pingwei},
abstractNote = {The recent outbreak of Zika virus (ZIKV) has infected over 1 million people in over 30 countries. ZIKV replicates its RNA genome using virally encoded replication proteins. Nonstructural protein 5 (NS5) contains a methyltransferase for RNA capping and a polymerase for viral RNA synthesis. Here we report the crystal structures of full-length NS5 and its polymerase domain at 3.0 Å resolution. The NS5 structure has striking similarities to the NS5 protein of the related Japanese encephalitis virus. The methyltransferase contains in-line pockets for substrate binding and the active site. Key residues in the polymerase are located in similar positions to those of the initiation complex for the hepatitis C virus polymerase. The polymerase conformation is affected by the methyltransferase, which enables a more efficiently elongation of RNA synthesis in vitro. Altogether, our results will contribute to future studies on ZIKV infection and the development of inhibitors of ZIKV replication.},
doi = {10.1038/ncomms14762},
journal = {Nature Communications},
number = ,
volume = 8,
place = {United States},
year = {Mon Mar 27 00:00:00 EDT 2017},
month = {Mon Mar 27 00:00:00 EDT 2017}
}

Journal Article:
Free Publicly Available Full Text
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Citation Metrics:
Cited by: 7works
Citation information provided by
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  • The rapid spread of the recentZika virus(ZIKV) epidemic across various countries in the American continent poses a major health hazard for the unborn fetuses of pregnant women. To date, there is no effective medical intervention. The nonstructural protein 5 ofZika virus(ZIKV-NS5) is critical for ZIKV replication through the 5'-RNA capping and RNA polymerase activities present in its N-terminal methyltransferase (MTase) and C-terminal RNA-dependent RNA polymerase (RdRp) domains, respectively. The crystal structure of the full-length ZIKV-NS5 protein has been determined at 3.05 Å resolution from a crystal belonging to space groupP2 12 12 and containing two protein molecules in the asymmetricmore » unit. The structure is similar to that reported for the NS5 protein fromJapanese encephalitis virusand suggests opportunities for structure-based drug design targeting either its MTase or RdRp domain.« less
  • 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. In conclusion, 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 antiviralsmore » for ZIKV.« less
  • Cited by 24
  • Genome cyclization is essential for flavivirus replication. We used RNases to probe the structures formed by the 5'-terminal 190 nucleotides and the 3'-terminal 111 nucleotides of the West Nile virus (WNV) genomic RNA. When analyzed individually, the two RNAs adopt stem-loop structures as predicted by the thermodynamic-folding program. However, when mixed together, the two RNAs form a duplex that is mediated through base-pairings of two sets of RNA elements (5'CS/3'CSI and 5'UAR/3'UAR). Formation of the RNA duplex facilitates a conformational change that leaves the 3'-terminal nucleotides of the genome (position - 8 to - 16) to be single-stranded. Viral NS5more » binds specifically to the 5'-terminal stem-loop (SL1) of the genomic RNA. The 5'SL1 RNA structure is essential for WNV replication. The study has provided further evidence to suggest that flavivirus genome cyclization and NS5/5'SL1 RNA interaction facilitate NS5 binding to the 3' end of the genome for the initiation of viral minus-strand RNA synthesis.« less