SARS-CoV-2 enzyme NendoU
ContentsFunctionUridylate-specific endoribonuclease (NendoU) SARS-CoV-2 non-structural protein 15 (Nsp15) is a nidoviral RNA uridylate-specific endoribonuclease (NendoU). Its C-terminal catalytic domain belongs to the EndoU family, meaning it produces 2’-3’ cyclic phosphodiester and 5’-hydroxytermini following RNA endonuclease activity on single- and double-stranded RNA and is specific for uridine [1]. Mn2+ dependence has been observed in other members of the NendoU subfamily. The exact functional relevance of Nsp15 is currently unknown. Nsp15-deficient corona viruses remain viable and replicating [2]. However, conflicting studies have been published on Nsp15’s role in interfering with the innate immune response [3],[4] and it has been suggested that Nsp15 degrades viral RNA as a method to hide it from host defences [2]. DiseaseSARS-CoV-2 is the cause of a global COVID-19 pandemic which started in 2019. RelevanceSARS-CoV-2 NendoU (Nsp15) represents a potential drug target for treatment of COVID-19, of particular interest is interfering with oligomerisation to prevent formation of the hexamer. Structural highlightsSARS-CoV-2 Nsp15 features three distinct domains. First, an N-terminal oligomerisation domain composed of an anti-parallel β-sheet (β1-3) wrapped around two helices (α1-2). This is followed by a middle domain made of three β-hairpins (β5-7, β7-8, and β12-13), a mixed β-sheet (β4, β9, β,10, β11, β15, and β15), and three α-helices (α3, η4, and α5). The final domain is the catalytic NendoU domain comprised of two anti-parallel β-sheets (β16-18 and β19-21) which form a concave surface flanked by five α-helices (α6-10). Six conserved residues make up the active site of Nsp15 (His235, His250, Lys290, Thr341, Tyr343, and Ser294) and are expected to coordinate a manganese ion. However, currently available structures have a magnesium ion modelled as manganese was not present in the crystallisation solution [2]. SARS-CoV-2 Nsp15 forms a hexamer of monomers. Each subunit domain contributes to the oligomer interface and the assembly is stabilised through interactions with the N-terminal oligomerisation domain. This forms a 100 Å long 10-15 Å wide channel down the three-fold axis which is open to solvent from the top, bottom and three separate side openings in the middle of the hexamer. SARS-CoV-2 Nsp15 from SARS-CoV-2 resembles previously observed endonucleases from SARS-CoV (0.52 Å RMSD, PDBID: 2H85) and MERS-CoV (1.16 Å RMSD, PDBID: 5YVD) [2]. See alsoCoronavirus_Disease 2019 (COVID-19) 3D structures of uridylate-specific endoribonucleaseUpdated on 17-February-2021 6vww, 6w01, 6xdh, 7k9p, 7keg, 7keh, 7kf4 – SCv2NendoU – SARS-CoV-2 2ozk, 2rhb, 4rs4, 4s1t – SCv2NendoU (mutant)
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