Abstract
SUMMARYThe Zika virus (ZIKV) poses a major public health emergency. To aid in the development of antivirals, we present two high-resolution crystal structures of the ZIKV NS5 methyltransferase: one bound to S-adenosylmethionine (SAM) and the other bound to SAM and 7-methyl guanosine diphosphate (7-MeGpp). We identify features of ZIKV NS5 methyltransferase that lend to structure-based antiviral drug discovery. Specifically, SAM analogs with functionalities on the Cβ atom of the methionine portion of the molecules that occupy the RNA binding tunnel may provide better specificity relative to human RNA methyltransferases.
Highlights
The Zika virus (ZIKV) is a member of the Flavivirus genus that includes other mosquitoborne human pathogens such as dengue virus (DENV1–4), Murray Valley encephalitis virus (MVEV), West Nile virus (WNV), yellow fever virus (YFV), and Japanese encephalitis virus (JEV), among others (Petersen et al, 2016)
The structures provide a basis for antiviral drug discovery
Its rapid spread across the Americas and, in particular, its link to microcephaly in newborn infants and the Guillain-Barré syndrome in adults has invigorated efforts to develop a vaccine against ZIKV and to eradicate the Aedes mosquito vectors
Summary
The Zika virus (ZIKV) is a member of the Flavivirus genus that includes other mosquitoborne human pathogens such as dengue virus (DENV1–4), Murray Valley encephalitis virus (MVEV), West Nile virus (WNV), yellow fever virus (YFV), and Japanese encephalitis virus (JEV), among others (Petersen et al, 2016). The flavivirus genome consists of an ~11 kB positive-sense single-stranded RNA that acquires a methylated 5′ cap structure (N7MeGpppA2′OMe; Me, methyl group) for stability, efficient translation, and evasion of the host immune response (Dong et al, 2014). Both the N7 and 2′O methylation reactions are performed by the same methyltransferase (MTase) domain, located at the N terminus of the nonstructural protein NS5. Crystal structures of several flavivirus NS5-MTases have been reported bound to various ligands (Bollati et al, 2009; Egloff et al, 2002, 2007; Yap et al, 2010; Zhao et al, 2015; Zhou et al, 2007), including SAM/SAH, GTP, and RNA
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have