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Structure and function of the NS5 methyltransferase domain from Usutu virus

DOI: 10.1016/j.antiviral.2022.105460 DOI Help

Authors: Diego S. Ferrero (Institut de Biologìa Molecular de Barcelona (IBMB-CSIC)) , Laura Albentosa-González (Universidad de Castilla-La Mancha) , Antonio Mas (Universidad de Castilla-La Mancha) , Nuria Verdaguer (Institut de Biologìa Molecular de Barcelona (IBMB-CSIC))
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Antiviral Research , VOL 208

State: Published (Approved)
Published: December 2022
Diamond Proposal Number(s): 19915

Abstract: 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.

Diamond Keywords: Usutu Virus; Viruses

Subject Areas: Biology and Bio-materials, Medicine

Instruments: I03-Macromolecular Crystallography

Other Facilities: ID30B at ESRF

Added On: 17/11/2022 09:31

Discipline Tags:

Pathogens Infectious Diseases Disease in the Developing World Health & Wellbeing Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)