English: Possible mechanisms of coordination between RNA synthesis and 5′-RNA capping. (A) Two possible mechanisms are proposed for 5′-RNA capping for (+) sense RNA. In a co-transcriptional model, 5′-RNA capping occurs co-transcriptionally while nascent (+) sense RNA is being synthesized from dsRNA replicative form. After a short stretch of (+) sense RNA being synthesized, the 5′ end of the nascent (+) RNA would be dephosphorylated by NS3 helicase, and capped and methylated by NS5 MTase. The cap structure is depicted with a closed circle. The 5′-capped (+) sense RNA would then be continuously synthesized until the entire (−) strand is copied. Upon completion of a cycle, a dsRNA containing a capped (+) strand and a capped (+) RNA are synthesized. In a post-transcriptional model, 5′-RNA capping occurs on the fully synthesized (+) strand RNA. Following strand separation of dsRNA, the (+) sense RNA could be dephoshphorylated by NS3 helicase, and capped and methylated by NS5 MTase. Upon completion of a cycle, a dsRNA and a capped (+) RNA are synthesized. (B) Coordination of RNA synthesis and 5′-RNA capping by flavivirus NS3 and NS5 in the post-transcriptional model. (i) NS3 helicase unwinds the dsRNA intermediate into (+) and (−) sense RNA, and hydrolyzes the 5′ end of (+) sense RNA by its 5′-RNA triphosphatase activity. (ii) The 3′ end of the (−) strand RNA will enter the NS5 RdRp template-binding channel, and serve as a template for (+) strand RNA synthesis. The 5′-dephosphorylated (+) RNA enters the NS5 MTase active site for 5′-RNA capping and methylations. (iii) Upon completion of nascent (+) sense RNA synthesis, a dsRNA and a 5′-capped (+) strand RNA are released from the NS5 RdRp and MTase domains. The dsRNA product, consisting of the (−) strand template and nascent (+) strand, is then recycled for another round of (+) strand RNA synthesis.