SARS-CoV-2 enzyme NendoU: Difference between revisions

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 == Function ==
 '''Uridylate-specific endoribonuclease (NendoU)'''
-Mn2+-dependent, uridylate-specific enzyme, which leaves 2'-3'-cyclic phosphates 5' to the cleaved bond.<ref>[https://zhanglab.ccmb.med.umich.edu/COVID-19/ Modeling of the SARS-COV-2 Genome]</ref><ref>pmid 32200634</ref>
+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 <ref>PMID:21422822</ref>. 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 <ref name="structure">PMID:32304108</ref>. However, conflicting studies have been published on Nsp15’s role in interfering with the innate immune response <ref>PMID:28484023</ref>,<ref>PMID:31351410</ref> and it has been suggested that Nsp15 degrades viral RNA as a method to hide it from host defences <ref name="structure" />.
 == Disease ==
+SARS-CoV-2 is the cause of a global COVID-19 pandemic which started in 2019.
 == Relevance ==
+SARS-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 highlights ==
+SARS-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 <ref name="structure" />.
+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) <ref name="structure" />.
 == See also ==