5m5b

Publication Abstract from PubMed

The Flavivirus Zika virus (ZIKV) is the causing agent of neurological disorders like microcephaly in newborns or Guillain-Barre syndrome. Its NS5 protein embeds a methyltransferase (MTase) domain involved in the formation of the viral mRNA cap. We investigated the structural and functional properties of the ZIKV MTase. We show that the ZIKV MTase can methylate RNA cap structures at the N7 position of the cap, and at the 2' O position on the ribose of the first nucleotide, yielding a cap-1 structure. In addition, the ZIKV MTase methylates the ribose 2' -O position of internal adenosines of RNA substrates. Crystal structure of the ZIKV MTase determined at 2.01 A resolution reveals a crystallographic homodimer. One chain is bound to the methyl-donor (SAM) and shows a high structural similarity to the Dengue virus (DENV) MTase. The second chain lacks SAM and displays conformational changes in the alphaX alpha-helix contributing to the SAM and RNA binding. These conformational modifications reveal a possible molecular mechanism of the enzymatic turnover involving a conserved Ser/Arg motif. In the second chain, the SAM binding site accommodates a sulphate close to a glycerol that could serve as a basis for structure-based drug design. In addition, compounds known to inhibit the DENV MTase show similar inhibition potency on the ZIKV MTase. Altogether these results contribute to a better understanding of the ZIKV MTase, a central player in viral replication and host innate immune response, and lay the basis development of potential antiviral drugs. IMPORTANCE: The Zika virus (ZIKV) is associated with microcephaly in newborns, and other neurological disorders such Guillain-Barre syndrome. It is urgent to developed antiviral strategies inhibiting the viral replication. The ZIKV NS5 embeds a methyltransferase involved in the viral mRNA capping process, which is essential for viral replication and control of virus detection by innate immune mechanisms. We demonstrate that the ZIKV methyltransferase methylates the mRNA cap and adenosines located into RNA sequences. The structure of ZIKV methyltransferase shows high structural similarities with the dengue virus methytransferase, but conformational specificities highlight the role of a conserved Ser/Arg motif, which participates to RNA and SAM recognition during the reaction turnover. In addition, the SAM binding site accommodates a sulphate and a glycerol, offering structural information to initiate structure based drug design. Altogether, these results contribute to a better understanding of the Flavivirus methytransferases, which are central players in the virus replication.

The Zika virus methyltransferase: structure and functions for drug design perspectives.,Coutard B, Barral K, Lichiere J, Selisko B, Martin B, Aouadi W, Ortiz Lombardia M, Debart F, Vasseur JJ, Guillemot JC, Canard B, Decroly E J Virol. 2016 Dec 28. pii: JVI.02202-16. doi: 10.1128/JVI.02202-16. PMID:28031359^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.