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Title: Structures of NS5 Methyltransferase from Zika Virus

Authors:
; ; ; ;
Publication Date:
Sponsoring Org.:
USDOE
OSTI Identifier:
1377995
Grant/Contract Number:
AC02-06CH11357
Resource Type:
Journal Article: Published Article
Journal Name:
Cell Reports
Additional Journal Information:
Journal Volume: 16; Journal Issue: 12; Related Information: CHORUS Timestamp: 2017-08-31 16:47:43; Journal ID: ISSN 2211-1247
Publisher:
Elsevier
Country of Publication:
Netherlands
Language:
English

Citation Formats

Coloma, Javier, Jain, Rinku, Rajashankar, Kanagalaghatta R., García-Sastre, Adolfo, and Aggarwal, Aneel K. Structures of NS5 Methyltransferase from Zika Virus. Netherlands: N. p., 2016. Web. doi:10.1016/j.celrep.2016.08.091.
Coloma, Javier, Jain, Rinku, Rajashankar, Kanagalaghatta R., García-Sastre, Adolfo, & Aggarwal, Aneel K. Structures of NS5 Methyltransferase from Zika Virus. Netherlands. doi:10.1016/j.celrep.2016.08.091.
Coloma, Javier, Jain, Rinku, Rajashankar, Kanagalaghatta R., García-Sastre, Adolfo, and Aggarwal, Aneel K. 2016. "Structures of NS5 Methyltransferase from Zika Virus". Netherlands. doi:10.1016/j.celrep.2016.08.091.
@article{osti_1377995,
title = {Structures of NS5 Methyltransferase from Zika Virus},
author = {Coloma, Javier and Jain, Rinku and Rajashankar, Kanagalaghatta R. and García-Sastre, Adolfo and Aggarwal, Aneel K.},
abstractNote = {},
doi = {10.1016/j.celrep.2016.08.091},
journal = {Cell Reports},
number = 12,
volume = 16,
place = {Netherlands},
year = 2016,
month = 9
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record at 10.1016/j.celrep.2016.08.091

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  • Two nonstructural proteins encoded byZika virusstrain MR766 RNA, a methyltransferase and a helicase, were crystallized and their structures were solved and refined at 2.10 and 2.01 Å resolution, respectively. The NS5 methyltransferase contains a boundS-adenosyl-L-methionine (SAM) co-substrate. The NS3 helicase is in the apo form. Comparison with published crystal structures of the helicase in the apo, nucleotide-bound and single-stranded RNA (ssRNA)-bound states suggests that binding of ssRNA to the helicase may occur through conformational selection rather than induced fit.
  • Zika flavivirus infection during pregnancy appears to produce higher risk of microcephaly, and also causes multiple neurological problems such as Guillain–Barré syndrome. The Zika virus is now widespread in Central and South America, and is anticipated to become an increasing risk in the southern United States. With continuing global travel and the spread of the mosquito vector, the exposure is expected to accelerate, but there are no currently approved treatments against the Zika virus. The Zika NS2B/NS3 protease is an attractive drug target due to its essential role in viral replication. Our studies have identified several compounds with inhibitory activitymore » (IC50) and binding affinity (KD) of ~5–10 μM against the Zika NS2B-NS3 protease from testing 71 HCV NS3/NS4A inhibitors that were initially discovered by high-throughput screening of 40,967 compounds. Competition surface plasmon resonance studies and mechanism of inhibition analyses by enzyme kinetics subsequently determined the best compound to be a competitive inhibitor with a Ki value of 9.5 μM. We also determined the X-ray structure of the Zika NS2B-NS3 protease in a “pre-open conformation”, a conformation never observed before for any flavivirus proteases. This provides the foundation for new structure-based inhibitor design.« less
  • 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