Structure and function of the NS5 methyltransferase domain from Usutu virus

Autor: Diego S. Ferrero, Laura Albentosa-González, Antonio Mas, Nuria Verdaguer
Přispěvatelé: Agencia Estatal de Investigación (España), Ministerio de Ciencia, Innovación y Universidades (España), Ministerio de Economía y Competitividad (España), Universidad de Castilla La Mancha
Rok vydání: 2022
Předmět:
Zdroj: Antiviral research. 208
ISSN: 1872-9096
Popis: Usutu virus (USUV), is a mosquito-borne flavivirus currently spreading outside the African continent producing substantial avian mortality. In contrast, infected humans could exhibit mild neurological symptoms or remain asymptomatic. As in other flaviviruses, the capped USUV genome encodes three structural and seven non-structural (NS) proteins. Among the NS proteins, NS5 plays crucial roles in virus replication, harbouring the capping and methyltransferase (MTase) activities in its N-terminal domain and the RNA-dependent RNA polymerase (RdRP) activity at the C-terminus. In this work, we present the first structural and functional characterization of the USUV MTase domain. The first structure of the USUV MTase has been determined in complex with its natural ligands (S-adenosyl-L-methionine [SAM]) and S-adenosyl-L-homocysteine [SAH]) at 2.2 Å resolution, showing a molecular dimer in the crystal asymmetric unit. One molecule is bound to the methyl donor SAM while the second is bound to the reaction by-product SAH. Both molecules are almost identical and also show a high structural similarity to the MTase domains of other flaviviruses. The structure of the USUV MTase bound to the inhibitor sinefungin at 1.8 Å resolution is also described. Careful comparisons of the interactions in the SAM-binding cavity prompt us to hypothesize about the strength and weakness of the structure-based design of antivirals directed to the SAM/SAH binding site that could be effective to deal with this threat.
The work at Prof. Nuria Verdaguer lab was funded by the Spanish Ministry of Science and Innovation (PID2020-117976GB-I00). The work at Prof. Antonio Mas was funded by Spanish Ministry of Science and Innovation (SAF2016-80451-P and PID2019-106068GB-I00) and UCLM (2019-GRIN-27080).
Databáze: OpenAIRE
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