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Article Dans Une Revue Nucleic Acids Research Année : 2023

Structural insights into viral genome replication by the severe fever with thrombocytopenia syndrome virus L protein

Résumé

Severe fever with thrombocytopenia syndrome virus (SFTSV) is a phenuivirus that has rapidly become endemic in several East Asian countries. The large (L) protein of SFTSV, which includes the RNAdependent RNA polymerase (RdRp), is responsible for catalysing viral genome replication and transcription. Here, we present 5 cryo-electron microscopy (cryo-EM) structures of the L protein in several states of the genome replication process, from pre-initiation to late-stage elongation, at a resolution of up to 2.6 Å. We identify how the L protein binds the 5 viral RNA in a hook-like conformation and show how the distal 5 and 3 RNA ends form a duplex positioning the 3 RNA terminus in the RdRp active site ready for initiation. We also observe the L protein stalled in the early and late stages of elongation with the RdRp core accommodating a 10-bp product-template duplex. This duplex ultimately splits with the template binding to a designated 3 secondary binding site. The structural data and observations are complemented by in vitro biochemical and cell-based mini-replicon assays. Altogether, our data provide novel key insights into the mechanism of viral genome replication by the SFTSV L protein and will aid drug development against segmented negative-strand RNA viruses.
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Dates et versions

hal-04300903 , version 1 (22-11-2023)

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Harry M. Williams, Sigurdur R. Thorkelsson, Dominik Vogel, Morlin Milewski, Carola Busch, et al.. Structural insights into viral genome replication by the severe fever with thrombocytopenia syndrome virus L protein. Nucleic Acids Research, 2023, 51 (3), pp.1424 - 1442. ⟨10.1093/nar/gkac1249⟩. ⟨hal-04300903⟩
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