Structural and Dynamic Characterization of Norovirus Protease

Abstract

Norovirus is a major etiologic agent of acute gastroenteritis outbreaks often occurring in confined, population-dense communities. Since neither vaccine nor antivirals are available to date, controlling norovirus infection presents significant challenges to public health. Norovirus protease (NVpro) plays a central role in the virus infectious cycle through a proteolytic maturation of nonstructural proteins that are not available in host cells. Therefore NVpro has been highlighted as a potential target for the antiviral drug development. While X-ray studies of the NVpro give us a wealth of the structural information including several key interactions for the substrate binding, the relevance of protein dynamics in the substrate biding and the ability to interact with multiple substrates has remained to be cleared. We present here the NMR solution structure and backbone dynamics of the protease from Norwalk virus, a prototype strain (GI.1) of norovirus. The bII-cII loop in C-terminal domain containing S2 binding site shows a nontrivial structural variation when compared to crystal structures and among lower energy structure ensemble. The possible biological implication of the observed dynamic properties of NVpro for the substrate recognition will be discussed.