Crystal structure of full-lengthZika virusNS5 protein reveals a conformation similar toJapanese encephalitis virusNS5

Anup K Upadhyay,Chaohong Sun,Matthew Cyr,Rakesh Tripathi,Dale J Kempf,Kenton Longenecker

doi:10.1107/s2053230x17001601

Anup K Upadhyay, Chaohong Sun + Show 4 more

Open Access

https://doi.org/10.1107/s2053230x17001601

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Abstract

The rapid spread of the recent Zika 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 of Zika 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 group P21212 and containing two protein molecules in the asymmetric unit. The structure is similar to that reported for the NS5 protein from Japanese encephalitis virus and suggests opportunities for structure-based drug design targeting either its MTase or RdRp domain.

Highlights

The spread of Zika virus (ZIKV) through more than 35 countries in the American continents over the past year has created a major public health emergency (Lessler et al, 2016; Hajra et al, 2016)
The cells were grown in Luria Broth (LB) medium containing 50 mg lÀ1 kanamycin and 34 mg lÀ1 chloramphenicol at 37C until the cell density (OD600) reached 0.4; the temperature was lowered to 16C
ZIKV is an example of several pathogenic human viruses that disproportionally affect people living in poverty with limited access to healthcare (Hotez et al, 2009)

Summary

Introduction

The spread of Zika virus (ZIKV) through more than 35 countries in the American continents over the past year has created a major public health emergency (Lessler et al, 2016; Hajra et al, 2016). ZIKV is spread primarily through Aedes albopictus and A. aegypti mosquito vectors, but can be sexually transmitted (Petersen et al, 2016; Weaver et al, 2016). Acute infection with ZIKV is often subclinical or, if symptomatic, typically associated with mild symptoms characteristic of acute viral infection. An increased risk of severe neurological disease, in particular Guillain–Barre syndrome, has been associated with ZIKV infection (Cao-Lormeau et al, 2016). ZIKV infection causes decreased male fertility in mice (Govero et al, 2016). Most concerning is the microcephaly associated with viral replication in human fetal brain tissue following perinatal transmission in pregnant women (Garcez et al, 2016; Broutet et al, 2016; Carteaux et al, 2016)

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