SARS-CoV-2 protein NSP15

Function

Uridylate-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].

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 ^[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 also

Coronavirus_Disease 2019 (COVID-19)
SARS-CoV-2_virus_proteins
COVID-19 AlphaFold2 Models

3D structures of uridylate-specific endoribonuclease

Updated on 14-February-2022

6vww, 6w01, 6xdh, 7k9p, 7keg, 7keh, 7kf4 – SCv2NendoU – SARS-CoV-2

2ozk, 2rhb, 4rs4, 4s1t – SCv2NendoU (mutant)
6wlc, 6x4i, 7k0r, 7k1l, 7k1o – SCv2NendoU + uridine derivative
5s6y, 5s72 – SCv2NendoU + urea derivative
5s71 – SCv2NendoU + thiothymidine
5s6x, 5s6z, 5s70 – SCv2NendoU + imidazole derivative
6wxc – SCv2NendoU + drug
6x1b – SCv2NendoU + DNA
5yvd – NendoU – MERS coronavirus