Comparative mechanistic studies of de novo RNA synthesis by flavivirus RNA-dependent RNA polymerases

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• 作者：Barbara Selisko ; Hé ; lè ; ne Dutartre ; Jean-Claude Guillemot ; Claire Debarnot ; Delphine Benarroch ; Alexander Khromykh ; Philippe Desprè ; s ; Marie-Pierre Egloff and Bruno Canard
• 关键词：Dengue virus ; Hepatitis C virus ; Flavivirus ; Flaviviridae ; RdRP ; Pestivirus ; Polymerase ; RNA synthesis ; West Nile virus
• 刊名：Virology
• 出版年：2006
• 出版时间：20 July 2006
• 年：2006
• 卷：351
• 期：1
• 页码：145-158
• 全文大小：907 K

文摘

Flavivirus protein NS5 harbors the RNA-dependent RNA polymerase (RdRp) activity. In contrast to the RdRps of hepaci- and pestiviruses, which belong to the same family of Flaviviridae, NS5 carries two activities, a methyltransferase (MTase) and a RdRp. RdRp domains of Dengue virus (DV) and West Nile virus (WNV) NS5 were purified in high yield relative to full-length NS5 and showed full RdRp activity. Steady-state enzymatic parameters were determined on homopolymeric template poly(rC). The presence of the MTase domain does not affect the RdRp activity. Flavivirus RdRp domains might bear more than one GTP binding site displaying positive cooperativity. The kinetics of RNA synthesis by four Flaviviridae RdRps were compared. In comparison to Hepatitis C RdRp, DV and WNV as well as Bovine Viral Diarrhea virus RdRps show less rate limitation by early steps of short-product formation. This suggests that they display a higher conformational flexibility upon the transition from initiation to elongation.