9hh6
From Proteopedia
(Difference between revisions)
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| - | '''Unreleased structure''' | ||
| - | + | ==Crystal Structure of Nsp15 Endoribonuclease from SARS CoV-2 in Complex with TAS-103== | |
| + | <StructureSection load='9hh6' size='340' side='right'caption='[[9hh6]], [[Resolution|resolution]] 2.00Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[9hh6]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Severe_acute_respiratory_syndrome_coronavirus_2 Severe acute respiratory syndrome coronavirus 2]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9HH6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9HH6 FirstGlance]. <br> | ||
| + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Hybrid , X-ray diffraction , X-ray solution scattering, [[Resolution|Resolution]] 2Å</td></tr> | ||
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1IUV:6-[2-(dimethylamino)ethylamino]-3-oxidanyl-indeno[2,1-c]quinolin-7-one'>A1IUV</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr> | ||
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=9hh6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9hh6 OCA], [https://pdbe.org/9hh6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9hh6 RCSB], [https://www.ebi.ac.uk/pdbsum/9hh6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9hh6 ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/A0A8B6RHF8_SARS2 A0A8B6RHF8_SARS2] Forms a primer, NSP9-pU, which is utilized by the polymerase for the initiation of RNA chains. Interacts with ribosome signal recognition particle RNA (SRP). Together with NSP8, suppress protein integration into the cell membrane, thereby disrupting host immune defenses.[ARBA:ARBA00043928] Plays a role in viral RNA synthesis through two distinct activities. The N7-guanine methyltransferase activity plays a role in the formation of the cap structure GpppA-RNA. The proofreading exoribonuclease reduces the sensitivity of the virus to RNA mutagens during replication. This activity acts on both ssRNA and dsRNA in a 3'-5' direction.[ARBA:ARBA00034456] RNA-directed RNA polymerase that catalyzes the transcription of viral genomic and subgenomic RNAs. Acts in complex with nsp7 and nsp8 to transcribe both the minus and positive strands of genomic RNA. The kinase-like NiRAN domain of NSP12 attaches one or more nucleotides to the amino terminus of NSP9, forming a covalent RNA-protein intermediate that serves as transcription/replication primer. Subgenomic RNAs (sgRNAs) are formed by discontinuous transcription: The polymerase has the ability to pause at transcription-regulating sequences (TRS) and jump to the leader TRS, resulting in a major deletion. This creates a series of subgenomic RNAs that are replicated, transcribed and translated. In addition, Nsp12 is a subunit of the viral RNA capping enzyme that catalyzes the RNA guanylyltransferase reaction for genomic and sub-genomic RNAs. Subsequently, the NiRAN domain transfers RNA to GDP, and forms the core cap structure GpppA-RNA.[ARBA:ARBA00043918] | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Since the emergence of SARS-CoV-2 at the end of 2019, the virus has caused significant global health and economic disruptions. Despite the rapid development of antiviral vaccines and some approved treatments such as remdesivir and paxlovid, effective antiviral pharmacological treatments for COVID-19 patients remain limited. This study explores Nsp15, a 3'-uridylate-specific RNA endonuclease, which has a critical role in immune system evasion and hence in escaping the innate immune sensors. We conducted a comprehensive drug repurposing screen and identified 44 compounds that showed more than 55% inhibition of Nsp15 activity in a real-time fluorescence assay. A validation pipeline was employed to exclude unspecific interactions, and dose-response assays confirmed 29 compounds with an IC(50) below 10 muM. Structural studies, including molecular docking and x-ray crystallography, revealed key interactions of identified inhibitors, such as TAS-103 and YM-155, with the Nsp15 active site and other critical regions. Our findings show that the identified compounds, particularly those retaining potency under different assay conditions, could serve as promising hits for developing Nsp15 inhibitors. Additionally, the study emphasizes the potential of combination therapies targeting multiple viral processes to enhance treatment efficacy and reduce the risk of drug resistance. This research contributes to the ongoing efforts to develop effective antiviral therapies for SARS-CoV-2 and possibly other coronaviruses. | ||
| - | + | Identification, validation, and characterization of approved and investigational drugs interfering with the SARS-CoV-2 endoribonuclease Nsp15.,Chatziefthymiou SD, Kuzikov M, Afandi S, Kovacs G, Srivastava S, Zaliani A, Gruzinov A, Pompidor G, Lunelli M, Ahmed GR, Labahn J, Hakanpaa J, Windshugel B, Kolbe M Protein Sci. 2025 Jun;34(6):e70156. doi: 10.1002/pro.70156. PMID:40371758<ref>PMID:40371758</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| + | <div class="pdbe-citations 9hh6" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Severe acute respiratory syndrome coronavirus 2]] | ||
| + | [[Category: Chatziefthymiou SD]] | ||
| + | [[Category: Hakanpaeae J]] | ||
| + | [[Category: Kolbe M]] | ||
| + | [[Category: Labahn J]] | ||
| + | [[Category: Windshuegel B]] | ||
Current revision
Crystal Structure of Nsp15 Endoribonuclease from SARS CoV-2 in Complex with TAS-103
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