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Structure paper

TitleAllosteric regulation and crystallographic fragment screening of SARS-CoV-2 NSP15 endoribonuclease.
Journal, issue, pagesNucleic Acids Res, Vol. 51, Issue 10, Page 5255-5270, Year 2023
Publish dateJun 9, 2023
AuthorsAndre Schutzer Godoy / Aline Minalli Nakamura / Alice Douangamath / Yun Song / Gabriela Dias Noske / Victor Oliveira Gawriljuk / Rafaela Sachetto Fernandes / Humberto D Muniz Pereira / Ketllyn Irene Zagato Oliveira / Daren Fearon / Alexandre Dias / Tobias Krojer / Michael Fairhead / Alisa Powell / Louise Dunnet / Jose Brandao-Neto / Rachael Skyner / Rod Chalk / Dávid Bajusz / Miklós Bege / Anikó Borbás / György Miklós Keserű / Frank von Delft / Glaucius Oliva /
PubMed AbstractSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19). The NSP15 endoribonuclease enzyme, known as NendoU, is highly conserved and ...Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19). The NSP15 endoribonuclease enzyme, known as NendoU, is highly conserved and plays a critical role in the ability of the virus to evade the immune system. NendoU is a promising target for the development of new antiviral drugs. However, the complexity of the enzyme's structure and kinetics, along with the broad range of recognition sequences and lack of structural complexes, hampers the development of inhibitors. Here, we performed enzymatic characterization of NendoU in its monomeric and hexameric form, showing that hexamers are allosteric enzymes with a positive cooperative index, and with no influence of manganese on enzymatic activity. Through combining cryo-electron microscopy at different pHs, X-ray crystallography and biochemical and structural analysis, we showed that NendoU can shift between open and closed forms, which probably correspond to active and inactive states, respectively. We also explored the possibility of NendoU assembling into larger supramolecular structures and proposed a mechanism for allosteric regulation. In addition, we conducted a large fragment screening campaign against NendoU and identified several new allosteric sites that could be targeted for the development of new inhibitors. Overall, our findings provide insights into the complex structure and function of NendoU and offer new opportunities for the development of inhibitors.
External linksNucleic Acids Res / PubMed:37115000 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution1.64 - 3.27 Å
Structure data

EMDB-23786, PDB-7me0:
Cryo-EM structure of SARS-CoV-2 NSP15 NendoU at pH 6.0
Method: EM (single particle) / Resolution: 2.48 Å

EMDB-24391, PDB-7rb0:
Cryo-EM structure of SARS-CoV-2 NSP15 NendoU at pH 7.5
Method: EM (single particle) / Resolution: 2.98 Å

EMDB-24392, PDB-7rb2:
Cryo-EM structure of SARS-CoV-2 NSP15 NendoU in BIS-Tris pH 6.0
Method: EM (single particle) / Resolution: 3.27 Å

PDB-5s6x:
PanDDA analysis group deposition -- Crystal Structure of SARS-CoV-2 NendoU in complex with Z2889976755
Method: X-RAY DIFFRACTION / Resolution: 2.32 Å

PDB-5s6y:
PanDDA analysis group deposition -- Crystal Structure of SARS-CoV-2 NendoU in complex with Z56900771
Method: X-RAY DIFFRACTION / Resolution: 2.32 Å

PDB-5s6z:
PanDDA analysis group deposition -- Crystal Structure of SARS-CoV-2 NendoU in complex with PB2255187532
Method: X-RAY DIFFRACTION / Resolution: 2.28 Å

PDB-5s70:
PanDDA analysis group deposition -- Crystal Structure of SARS-CoV-2 NendoU in complex with EN300-181428
Method: X-RAY DIFFRACTION / Resolution: 2.327 Å

PDB-5s71:
PanDDA analysis group deposition -- Crystal Structure of SARS-CoV-2 NendoU in complex with FUZS-5
Method: X-RAY DIFFRACTION / Resolution: 1.941 Å

PDB-5s72:
PanDDA analysis group deposition -- Crystal Structure of SARS-CoV-2 NendoU in complex with BBL029427
Method: X-RAY DIFFRACTION / Resolution: 2.512 Å

PDB-5sa4:
PanDDA analysis group deposition -- Crystal Structure of SARS-CoV-2 NendoU in complex with Z239136710
Method: X-RAY DIFFRACTION / Resolution: 2.046 Å

PDB-5sa5:
PanDDA analysis group deposition -- Crystal Structure of SARS-CoV-2 NendoU in complex with Z1530301542
Method: X-RAY DIFFRACTION / Resolution: 2.09 Å

PDB-5sa6:
PanDDA analysis group deposition -- Crystal Structure of SARS-CoV-2 NendoU in complex with Z2856434783
Method: X-RAY DIFFRACTION / Resolution: 2.517 Å

PDB-5sa7:
PanDDA analysis group deposition -- Crystal Structure of SARS-CoV-2 NendoU in complex with Z1673618163
Method: X-RAY DIFFRACTION / Resolution: 2.222 Å

PDB-5sa8:
PanDDA analysis group deposition -- Crystal Structure of SARS-CoV-2 NendoU in complex with Z68299550
Method: X-RAY DIFFRACTION / Resolution: 2.298 Å

PDB-5sa9:
PanDDA analysis group deposition -- Crystal Structure of SARS-CoV-2 NendoU in complex with Z2697514548
Method: X-RAY DIFFRACTION / Resolution: 1.92 Å

PDB-5saa:
PanDDA analysis group deposition -- Crystal Structure of SARS-CoV-2 NendoU in complex with Z319891284
Method: X-RAY DIFFRACTION / Resolution: 2.239 Å

PDB-5sab:
PanDDA analysis group deposition -- Crystal Structure of SARS-CoV-2 NendoU in complex with Z31504642
Method: X-RAY DIFFRACTION / Resolution: 2.486 Å

PDB-5sac:
PanDDA analysis group deposition -- Crystal Structure of SARS-CoV-2 NendoU in complex with Z59181945
Method: X-RAY DIFFRACTION / Resolution: 2.029 Å

PDB-5sad:
PanDDA analysis group deposition -- Crystal Structure of SARS-CoV-2 NendoU in complex with Z425449682
Method: X-RAY DIFFRACTION / Resolution: 1.961 Å

PDB-5sae:
PanDDA analysis group deposition -- Crystal Structure of SARS-CoV-2 NendoU in complex with Z3219959731
Method: X-RAY DIFFRACTION / Resolution: 2.12 Å

PDB-5saf:
PanDDA analysis group deposition -- Crystal Structure of SARS-CoV-2 NendoU in complex with EN300-321461
Method: X-RAY DIFFRACTION / Resolution: 2.11 Å

PDB-5sag:
PanDDA analysis group deposition -- Crystal Structure of SARS-CoV-2 NendoU in complex with EN300-1605072
Method: X-RAY DIFFRACTION / Resolution: 1.881 Å

PDB-5sah:
PanDDA analysis group deposition -- Crystal Structure of SARS-CoV-2 NendoU in complex with EN300-100112
Method: X-RAY DIFFRACTION / Resolution: 2.16 Å

PDB-5sai:
PanDDA analysis group deposition -- Crystal Structure of SARS-CoV-2 NendoU in complex with Z1424343998
Method: X-RAY DIFFRACTION / Resolution: 2.022 Å

PDB-5sbf:
PanDDA analysis group deposition of ground-state model of SARS-CoV-2 NendoU
Method: X-RAY DIFFRACTION / Resolution: 1.64 Å

PDB-7keg:
Crystal structure from SARS-COV2 NendoU NSP15
Method: X-RAY DIFFRACTION / Resolution: 2.9 Å

PDB-7keh:
Crystal structure from SARS-CoV-2 NendoU NSP15
Method: X-RAY DIFFRACTION / Resolution: 2.59 Å

PDB-7kf4:
Crystal structure from SARS-CoV-2 NendoU NSP15
Method: X-RAY DIFFRACTION / Resolution: 2.61 Å

PDB-7n7r:
Crystal Structure of SARS-CoV-2 NendoU in complex with Z2472938267
Method: X-RAY DIFFRACTION / Resolution: 2.01 Å

PDB-7n7u:
Crystal Structure of SARS-CoV-2 NendoU in complex with LIZA-7
Method: X-RAY DIFFRACTION / Resolution: 2.06 Å

PDB-7n7w:
Crystal Structure of SARS-CoV-2 NendoU in complex with CSC000178569
Method: X-RAY DIFFRACTION / Resolution: 2.42 Å

PDB-7n7y:
Crystal Structure of SARS-CoV-2 NendoU in complex with Z18197050
Method: X-RAY DIFFRACTION / Resolution: 2.09 Å

PDB-7n83:
Crystal Structure of SARS-CoV-2 NendoU in complex with Z2443429438
Method: X-RAY DIFFRACTION / Resolution: 1.91 Å

Chemicals

ChemComp-CIT:
CITRIC ACID

ChemComp-WUG:
1-(2,4-dimethyl-1H-imidazol-5-yl)methanamine

ChemComp-HOH:
WATER

ChemComp-WUJ:
N-[(furan-2-yl)methyl]urea

ChemComp-WUM:
4-[(dimethylamino)methyl]-1,3-thiazol-2-amine

ChemComp-WUS:
(5R)-2-methyl-4,5,6,7-tetrahydro-1H-benzimidazol-5-amine

ChemComp-WUV:
5'-thiothymidine

ChemComp-WUY:
N-(2-aminoethyl)-N'-phenylurea

ChemComp-K3A:
N-(5-methyl-1H-pyrazol-3-yl)acetamide

ChemComp-ZQA:
4-ethyl-2-(1H-imidazol-5-yl)-1,3-thiazole

ChemComp-O3G:
N-benzyl-1-(4-fluorophenyl)methanamine

ChemComp-WL7:
4-amino-N-(2-hydroxyethyl)-N-methylbenzene-1-sulfonamide

ChemComp-JOV:
3-chloro-N-(1-hydroxy-2-methylpropan-2-yl)benzamide

ChemComp-GWG:
1-methylindazole-3-carboxamide

ChemComp-ZQD:
3-[(2S)-1-(methanesulfonyl)pyrrolidin-2-yl]-5-methyl-1,2-oxazole

ChemComp-WJD:
2-methoxy-N-phenylacetamide

ChemComp-VWG:
N-hydroxyquinoline-2-carboxamide

ChemComp-EJW:
(3-phenyl-1,2-oxazol-5-yl)methylazanium

ChemComp-W3G:
pyridazin-3(2H)-one

ChemComp-WOY:
6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine

ChemComp-ZQG:
3-(1H-imidazol-2-yl)propan-1-amine

ChemComp-ZQJ:
2-methyl-5,6,7,8-tetrahydropyrido[4,3-c]pyridazin-3(2H)-one

ChemComp-ZQM:
N-{2-[(propan-2-yl)sulfanyl]phenyl}urea

ChemComp-PO4:
PHOSPHATE ION

ChemComp-B3P:
2-[3-(2-HYDROXY-1,1-DIHYDROXYMETHYL-ETHYLAMINO)-PROPYLAMINO]-2-HYDROXYMETHYL-PROPANE-1,3-DIOL / pH buffer*YM

ChemComp-SO4:
SULFATE ION

ChemComp-S6V:
1-[2-(2-oxidanylidenepyrrolidin-1-yl)ethyl]-3-phenyl-urea

ChemComp-0MI:
1-[(2~{R},4~{S},5~{R})-5-[[(azanylidene-$l^{4}-azanylidene)amino]methyl]-4-oxidanyl-oxolan-2-yl]-5-methyl-pyrimidine-2,4-dione

ChemComp-0OI:
N-(2-fluorophenyl)-N'-methylurea

ChemComp-RZG:
methyl 4-sulfamoylbenzoate

ChemComp-WNM:
(3S)-1-(phenylsulfonyl)pyrrolidin-3-amine

Source
  • severe acute respiratory syndrome coronavirus 2
KeywordsHYDROLASE / SGC - Diamond I04-1 fragment screening / PanDDA / XChemExplorer / nsp15 / nendoU / sars-cov-2 / sars / covid / covid19 / HYDROLASE/HYDROLASE inhibitor / HYDROLASE-HYDROLASE inhibitor complex / VIRAL PROTEIN / covid-19 / endoribonuclease / coronavirus

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