SARS-CoV-2 enzyme NendoU
From Proteopedia
FunctionUridylate-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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References
- ↑ Ulferts R, Ziebuhr J. Nidovirus ribonucleases: Structures and functions in viral replication. RNA Biol. 2011 Mar-Apr;8(2):295-304. doi: 10.4161/rna.8.2.15196. Epub 2011 Mar 1. PMID:21422822 doi:http://dx.doi.org/10.4161/rna.8.2.15196
- ↑ 2.0 2.1 2.2 2.3 Kim Y, Jedrzejczak R, Maltseva NI, Wilamowski M, Endres M, Godzik A, Michalska K, Joachimiak A. Crystal structure of Nsp15 endoribonuclease NendoU from SARS-CoV-2. Protein Sci. 2020 Apr 17. doi: 10.1002/pro.3873. PMID:32304108 doi:http://dx.doi.org/10.1002/pro.3873
- ↑ Deng X, Hackbart M, Mettelman RC, O'Brien A, Mielech AM, Yi G, Kao CC, Baker SC. Coronavirus nonstructural protein 15 mediates evasion of dsRNA sensors and limits apoptosis in macrophages. Proc Natl Acad Sci U S A. 2017 May 23;114(21):E4251-E4260. doi:, 10.1073/pnas.1618310114. Epub 2017 May 8. PMID:28484023 doi:http://dx.doi.org/10.1073/pnas.1618310114
- ↑ Liu X, Fang P, Fang L, Hong Y, Zhu X, Wang D, Peng G, Xiao S. Porcine deltacoronavirus nsp15 antagonizes interferon-beta production independently of its endoribonuclease activity. Mol Immunol. 2019 Oct;114:100-107. doi: 10.1016/j.molimm.2019.07.003. Epub 2019, Jul 24. PMID:31351410 doi:http://dx.doi.org/10.1016/j.molimm.2019.07.003
