Structures of dengue virus RNA replicase complexes

Dengue is a mosquito-borne viral infection caused by dengue virus (DENV), a member of the flaviviruses. The DENV genome is a 5'-capped positive-sense RNA with a unique 5'-stem-loop structure (SLA), which is essen-tial for RNA replication and 5' capping. The virus-encoded proteins NS5 and NS3 are responsible for viral genome replication, but the structural basis by which they cooperatively conduct the required tasks has re-mained unclear. Here, we report the cryoelectron microscopy (cryo-EM) structures of SLA-bound NS5 (PC), NS3-bound PC (PC-NS3), and an RNA-elongating NS5-NS3 complex (EC). While SLA bridges the NS5 meth-yltransferase and RNA-dependent RNA polymerase domains in PC, the NS3 helicase domain displaces it in elongation complex (EC). The SLA-and NS3-binding sites overlap with that of human STAT2. These struc-tures illuminate the key steps in DENV genome replication, namely, SLA-dependent replication initiation, processive RNA elongation, and 5' capping of the nascent genomic RNA, thereby providing foundations to combat flaviviruses.

Automated summary

Dengue is a mosquito-borne viral infection caused by dengue virus (DENV). The cryoelectron microscopy (cryo-EM) structures of DENV genome replication process have been revealed, which include SLA-bound NS5, NS3-bound PC, and an RNA-elongating NS5-NS3 complex. These structures shed light on the key steps of DENV genome replication, providing foundations for combating flaviviruses.