In the past two years, the collaborative research teams led by Prof. Peng Gong and Prof. Bo Zhang have published three papers focusing on the regulation between the methyltranferase and polymerase modules of flavivirus NS5. Since the report of the first flavivirus NS5 methyltransferase crystal structure (EMBO J 2002), scientists have made tremendous efforts in getting a full-length structure also including the polymerase. The breakthrough was made by the Gong group that reported the first full-length crystal structure revealing a conserved interface between the two enzyme modules (PLoS Pathog 2013). Soon after, the Zhang Group validated the function of the interface in the level of virus replication and discovered novel sites that may also participate in the auto-regulation of NS5 (PLoS Negl Trop Dis 2014). To more specifically address the interface regulation on polymerase catalysis, recombinant NS5 and its interface mutants were compared in finely designed polymerase assays. The data suggested that the interface interactions were relevant in both initiation and elongation of RNA synthesis (J Virol 2015). Collectively, the work done by these two groups has made significant contribution to the understanding of NS5 that plays key roles in flavivirus life cycle.