The March 27 issue of Nature Communications will include an important structure from the lab of Prof. Pingwei Li in the Dept. of Biochemistry and Biophyics at Texas A&M.
Zika virus (ZIKV) is causing a global public health emergency. ZIKV infection, spread by mosquitos, is linked to severe congenital diseases and high incidence of Guillan-Barré syndrome. Currently, there are no effective vaccines or therapeutics to control or treat ZIKV infection. The ZIKV nonstructural protein 5 (NS5) is an attractive target for anti-Zika drug design because it is essential for the replication of the viral RNA genome. The N-terminal portion of NS5 contains a methyltransferase (MT) for RNA capping, followed by a short 10 amino acid linker that connects to a C-terminal RNA-dependent RNA polymerase (RdRp). In collaboration with Dr. Cheng Kao‘s lab at Indiana University, Dr. Baoyu Zhao, post-doctoral scholar from the Li lab, determined the crystal structures of ZIKV full-length NS5 and its polymerase domain at 3.0 Å resolution. Although the overall structure of the ZIKV NS5 is similar to the RNA polymerases of other viruses of the Flaviviridae family, it shows significant structural differences in the RdRp, which can be targeted for designing inhibitors specific for ZIKV. Li’s group and their collaborators observed that the conformation of the RdRp domain of ZIKV NS5 is influenced by the MT domain, which enables more efficiently elongation of RNA synthesis in vitro. These structural studies will contribute significantly to future studies on ZIKV infection and the development of antiviral agents to suppress ZIKV replication.
The picture shows the structure of full-length ZIKV NS5 in two different orientations over the organization of the NS5 gene.