title: A structural view of the RNA-dependent RNA polymerases from the Flavivirus genus.
abstract: The RNA-dependent RNA polymerase (RdRP) from the Flavivirus genus is naturally fused to a methyltransferase (MTase), and the full-length protein is named nonstructural protein 5 (NS5). Similar to polymerases from other RNA viruses, the flavivirus RdRP has an encircled human right hand architecture with palm, fingers, and thumb domains surrounding its polymerase active site. In contrast to primer-dependent RdRPs that have a spacious front channel to accommodate the template-product RNA duplex, the flavivirus RdRP has a priming element as a thumb domain insertion, partially occupying the front channel to facilitate the de novo initiation process. Seven catalytic motifs A through G have been identified for all viral RdRPs and have highly homologous spatial arrangement around the active site despite low sequence conservation in several motifs if considering all viral families, forming an important basis to the understandings of the common features for viral RdRPs. In the two different global conformations identified in full-length crystal structures of Japanese encephalitis virus (JEV) and Dengue virus (DENV) NS5 proteins, the MTase approaches the RdRP consistently from the backside but its orientation and the interaction details with the RdRP are drastically different. Further investigations are required to clarify the conservation, functional relevance, and relationship of these conformations. Remaining challenges with respect to flavivirus RdRP structure are also discussed.
authors.affiliation: Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, No. 44 Xiao Hong Shan, Wuhan, Hubei 430071, China.
authors.forename: Guoliang
authors.initials: G
authors.lastname: Lu
authors.affiliation: Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, No. 44 Xiao Hong Shan, Wuhan, Hubei 430071, China. Electronic address: gongpeng@wh.iov.cn.
authors.forename: Peng
authors.initials: P
authors.lastname: Gong
mesh_terms: D020134:Catalytic Domain; D017124:Conserved Sequence; D003716:Dengue Virus / Q000201:enzymology*; D018349:Encephalitis Viruses, Japanese / Q000201:enzymology*; D006801:Humans; D008780:Methyltransferases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011487:Protein Conformation; D012324:RNA-Dependent RNA Polymerase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid
chemical_list: D008780:Methyltransferases; D012324:RNA-Dependent RNA Polymerase
keywords: Catalytic motif; Flavivirus; Methyltransferase; RNA-dependent RNA polymerase; de novo initiation