Proteopedia - User contributions [en]

SARS-CoV-2 enzyme NendoU

2020-06-03T10:46:20Z

Sam Horrell:

<Structure load='6VWW' size='350' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' /><SX viewer='molstar' load='' size='340' side='right' caption='' scene=''>

== 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 <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 ==
[[Coronavirus_Disease 2019 (COVID-19)]]
__NOTOC__
</SX>
== References ==
<references/>

SARS-CoV-2 enzyme NendoU

2020-06-03T10:44:17Z

Sam Horrell:

<SX viewer='molstar' load='' size='340' side='right' caption='' scene=''>

== 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 <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 ==
[[Coronavirus_Disease 2019 (COVID-19)]]
__NOTOC__
</SX>
== References ==
<references/>

SARS-CoV-2 enzyme NendoU

2020-06-03T10:38:51Z

Sam Horrell:

<SX viewer='molstar' load='' size='340' side='right' caption='' scene=''>
{{Theoretical_model}}
== 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 <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 ==
[[Coronavirus_Disease 2019 (COVID-19)]]
__NOTOC__
</SX>
== References ==
<references/>

SARS-CoV-2 enzyme NendoU

2020-06-03T10:38:02Z

Sam Horrell: