Crystal Structure of the RNA Polymerase Domain of the West Nile Virus Non-Structural Protein 5

H Malet, M-P Egloff, B Selisko, RE Butcher, PJ Wright, M Roberts, A Gruez, G Sulzenbacher, C Vonrhein, G Bricogne, JM Mackenzie, AA Khromykh, AD Davidson, B Canard

Research output: Contribution to journalArticle (Academic Journal)peer-review

183 Citations (Scopus)

Abstract

Viruses of the family Flaviviridae are important human and animal pathogens. Among them, the Flaviviruses dengue (DENV) and West Nile (WNV) cause regular outbreaks with fatal outcomes. The RNA-dependent RNA polymerase (RdRp) activity of the non-structural protein 5 (NS5) is a key activity for viral RNA replication. In this study, crystal structures of enzymatically active and inactive WNV RdRp domains were determined at 3.0- and 2.35-AÅ resolution, respectively. The determined structures were shown to be mostly similar to the RdRps of the Flaviviridae members hepatitis C and bovine viral diarrhea virus, although with unique elements characteristic for the WNVRdRp. Using a reverse genetic system, residues involved in putative interactions between the RNA-cap methyltransferase (MTase) and the RdRp domain of Flavivirus NS5 were identified. This allowed us to propose a model for the structure of the full-length WNV NS5 by in silico docking of the WNV MTase domain (modeled from our previously determined structure of the DENV MTase domain) onto the RdRp domain. The Flavivirus RdRp domain structure determined here should facilitate both the design of anti-Flavivirus drugs and structure-function studies of the Flavivirus replication complex in which the multifunctional NS5 protein plays a central role.
Translated title of the contributionCrystal Structure of the RNA Polymerase Domain of the West Nile Virus Non-Structural Protein 5
Original languageEnglish
Pages (from-to)10678 - 10689
Number of pages12
JournalJournal of Biological Chemistry
Volume282 (14)
DOIs
Publication statusPublished - Apr 2007

Bibliographical note

Publisher: The American Society for Biochemistry and Molecular Biology

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