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Structure and function of the Toscana virus cap-snatching endonuclease

Abstract : Toscana virus (TOSV) is an arthropod-borne human pathogen responsible for seasonal outbreaks of fever and meningoencephalitis in the Mediterranean basin. TOSV is a segmented negative-strand RNA virus (sNSV) that belongs to the genus phlebovirus (family Phenuiviridae, order Bunyavirales), encompassing other important human pathogens such as Rift Valley fever virus (RVFV). Here, we carried out a structural and functional characterization of the TOSV cap-snatching endonuclease, an N terminal domain of the viral polymerase (L protein) that provides capped 3 OH primers for transcription. We report TOSV endonuclease crystal structures in the apo form, in complex with a di-ketoacid inhibitor (DPBA) and in an intermediate state of inhibitor release , showing details on substrate binding and active site dynamics. The structure reveals substantial folding rearrangements absent in previously reported cap-snatching endonucleases. These include the relocation of the N terminus and the appearance of new structural motifs important for transcription and replication. The enzyme shows high activity rates comparable to other His+ cap-snatching en-donucleases. Moreover, the activity is dependent on conserved residues involved in metal ion and sub-strate binding. Altogether, these results bring new light on the structure and function of cap-snatching endonucleases and pave the way for the development of specific and broad-spectrum antivirals.
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Rhian Jones, Sana Lessoued, Kristina Meier, Stéphanie Devignot, Sergio Barata-García, et al.. Structure and function of the Toscana virus cap-snatching endonuclease. Nucleic Acids Research, Oxford University Press, 2019, 47, pp.10914-10930. ⟨10.1093/nar/gkz838⟩. ⟨hal-02611184⟩

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