Structure of the NS5 methyltransferase from Zika virus and implications in inhibitor design

Biochem Biophys Res Commun. 2017 Oct 28;492(4):624-630. doi: 10.1016/j.bbrc.2016.11.098. Epub 2016 Nov 17.

Abstract

Recent outbreak of flavivirus Zika virus (ZIKV) in America has urged the basic as well as translational studies of this important human pathogen. The nonstructural protein 5 (NS5) of the flavivirus has an N-terminal methyltransferase (MTase) domain that plays critical roles in viral RNA genome capping. The null mutant of NS5 MTase is lethal for virus. Therefore, NS5 is a potential drug target for the treatment of Zika virus infection. In this study, we determined crystal structures of the ZIKV MTase in complex with GTP and RNA cap analogue 7meGpppA. Structural analyses revealed highly conserved GTP/cap-binding pocket and S-adenosylmethionine (SAM)-binding pocket. Two conformations of the second base of the cap were identified, which suggests the flexibility of RNA conformation. In addition, the ligand-binding pockets identified a continuous region of hotspots suitable for drug design. Docking calculation shows that the Dengue virus inhibitor compound 10 may bind to the ZIKV MTase.

Keywords: Antiviral inhibitor design; Flavivirus family virus; Methyltransferase; RNA cap; Zika virus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Drug Design
  • Enzyme Inhibitors / chemistry*
  • Models, Molecular*
  • Molecular Docking Simulation*
  • Protein Binding
  • Protein Conformation
  • Viral Nonstructural Proteins / antagonists & inhibitors
  • Viral Nonstructural Proteins / chemistry*
  • Viral Nonstructural Proteins / ultrastructure*
  • Zika Virus / enzymology*

Substances

  • Enzyme Inhibitors
  • NS5 protein, flavivirus
  • Viral Nonstructural Proteins