Please use this identifier to cite or link to this item: https://hdl.handle.net/10356/82917
Title: Molecular basis for specific viral RNA recognition and 2' -O-ribose methylation by the dengue virus nonstructural protein 5 (NS5)
Authors: Zhao, Yongqian
Soh, Tingjin Sherryl
Lim, Siew Pheng
Chung, Ka Yan
Swaminathan, Kunchithapadam
Vasudevan, Subhash G.
Shi, Pei-Yong
Lescar, Julien
Luo, Dahai
Keywords: 2′-O-ribose methyltransferase
Dengue virus
Nonstructural protein 5 methyltransferase-polymerase
Cap-0 RNA
Innate immunity evasion
Issue Date: 2015
Source: Zhao, Y., Soh, T. S., Lim, S. P., Chung, K. Y., Swaminathan, K., Vasudevan, S. G., et al. (2015). Molecular basis for specific viral RNA recognition and 2'-O-ribose methylation by the dengue virus nonstructural protein 5 (NS5). Proceedings of the National Academy of Sciences of the United States of America, 112(48), 14834-14839.
Series/Report no.: Proceedings of the National Academy of Sciences of the United States of America
Abstract: Dengue virus (DENV) causes several hundred million human infections and more than 20,000 deaths annually. Neither an efficacious vaccine conferring immunity against all four circulating serotypes nor specific drugs are currently available to treat this emerging global disease. Capping of the DENV RNA genome is an essential structural modification that protects the RNA from degradation by 5′ exoribonucleases, ensures efficient expression of viral proteins, and allows escape from the host innate immune response. The large flavivirus nonstructural protein 5 (NS5) (105 kDa) has RNA methyltransferase activities at its N-terminal region, which is responsible for capping the virus RNA genome. The methyl transfer reactions are thought to occur sequentially using the strictly conserved flavivirus 5′ RNA sequence as substrate (GpppAG-RNA), leading to the formation of the 5′ RNA cap: G0pppAG-RNA→m7G0pppAG-RNA (“cap-0”)→m7G0pppAm2′-O-G-RNA (“cap-1”). To elucidate how viral RNA is specifically recognized and methylated, we determined the crystal structure of a ternary complex between the full-length NS5 protein from dengue virus, an octameric cap-0 viral RNA substrate bearing the authentic DENV genomic sequence (5′-m7G0pppA1G2U3U4G5U6U7-3′), and S-adenosyl-l-homocysteine (SAH), the by-product of the methylation reaction. The structure provides for the first time, to our knowledge, a molecular basis for specific adenosine 2′-O-methylation, rationalizes mutagenesis studies targeting the K61-D146-K180-E216 enzymatic tetrad as well as residues lining the RNA binding groove, and offers previously unidentified mechanistic and evolutionary insights into cap-1 formation by NS5, which underlies innate immunity evasion by flaviviruses.
URI: https://hdl.handle.net/10356/82917
http://hdl.handle.net/10220/40374
ISSN: 1091-6490
DOI: 10.1073/pnas.1514978112
Rights: © 2015 The Author(s) (Published by National Academy of Sciences). This is the author created version of a work that has been peer reviewed and accepted for publication by Proceedings of the National Academy of Sciences of the United States of America, The Author(s) (Published by National Academy of Sciences). It incorporates referee’s comments but changes resulting from the publishing process, such as copyediting, structural formatting, may not be reflected in this document. The published version is available at: [http://dx.doi.org/10.1073/pnas.1514978112].
Fulltext Permission: open
Fulltext Availability: With Fulltext
Appears in Collections:LKCMedicine Journal Articles
SBS Journal Articles

Files in This Item:
File Description SizeFormat 
Molecular basis for specific viral RNA recognition.pdf2.57 MBAdobe PDFThumbnail
View/Open

SCOPUSTM   
Citations 20

36
checked on Sep 5, 2020

WEB OF SCIENCETM
Citations 50

34
checked on Oct 16, 2020

Page view(s) 50

299
checked on Oct 21, 2020

Download(s) 50

50
checked on Oct 21, 2020

Google ScholarTM

Check

Altmetric


Plumx

Items in DR-NTU are protected by copyright, with all rights reserved, unless otherwise indicated.