6w2a
From Proteopedia
(Difference between revisions)
| Line 1: | Line 1: | ||
==1.65 A resolution structure of SARS-CoV 3CL protease in complex with inhibitor 7j== | ==1.65 A resolution structure of SARS-CoV 3CL protease in complex with inhibitor 7j== | ||
| - | <StructureSection load='6w2a' size='340' side='right'caption='[[6w2a]]' scene=''> | + | <StructureSection load='6w2a' size='340' side='right'caption='[[6w2a]], [[Resolution|resolution]] 1.65Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6W2A OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6W2A FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6w2a]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Cvhsa Cvhsa]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6W2A OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6W2A FirstGlance]. <br> |
| - | </td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6w2a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6w2a OCA], [http://pdbe.org/6w2a PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6w2a RCSB], [http://www.ebi.ac.uk/pdbsum/6w2a PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6w2a ProSAT]</span></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=QYS:(1S,2S)-2-[(N-{[(4,4-difluorocyclohexyl)methoxy]carbonyl}-L-leucyl)amino]-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propane-1-sulfonic+acid'>QYS</scene>, <scene name='pdbligand=VDJ:[4,4-bis(fluoranyl)cyclohexyl]methyl+~{N}-[(2~{S})-1-[[(1~{R},2~{S})-1-[bis(oxidanyl)-oxidanylidene-$l^{5}-sulfanyl]-1-oxidanyl-3-[(3~{S})-2-oxidanylidenepyrrolidin-3-yl]propan-2-yl]amino]-4-methyl-1-oxidanylidene-pentan-2-yl]carbamate'>VDJ</scene></td></tr> |
| + | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">1a ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=694009 CVHSA])</td></tr> | ||
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6w2a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6w2a OCA], [http://pdbe.org/6w2a PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6w2a RCSB], [http://www.ebi.ac.uk/pdbsum/6w2a PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6w2a ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| + | == Function == | ||
| + | [[http://www.uniprot.org/uniprot/R1A_CVHSA R1A_CVHSA]] The papain-like proteinase (PL-PRO) is responsible for the cleavages located at the N-terminus of replicase polyprotein. In addition, PL-PRO possesses a deubiquitinating/deISGylating activity and processes both 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains from cellular substrates. Antagonizes innate immune induction of type I interferon by blocking the phosphorylation, dimerization and subsequent nuclear translocation of host IRF-3.<ref>PMID:17024178</ref> <ref>PMID:17692280</ref> <ref>PMID:19369340</ref> The main proteinase 3CL-PRO is responsible for the majority of cleavages as it cleaves the C-terminus of replicase polyprotein at 11 sites. Recognizes substrates containing the core sequence [ILMVF]-Q-|-[SGACN]. Inhibited by the substrate-analog Cbz-Val-Asn-Ser-Thr-Leu-Gln-CMK (By similarity). Also contains an ADP-ribose-1''-phosphate (ADRP)-binding function.<ref>PMID:17024178</ref> <ref>PMID:17692280</ref> <ref>PMID:19369340</ref> Nsp7-nsp8 hexadecamer may possibly confer processivity to the polymerase, maybe by binding to dsRNA or by producing primers utilized by the latter.<ref>PMID:17024178</ref> <ref>PMID:17692280</ref> <ref>PMID:19369340</ref> Nsp9 is a ssRNA-binding protein.<ref>PMID:17024178</ref> <ref>PMID:17692280</ref> <ref>PMID:19369340</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Pathogenic coronaviruses are a major threat to global public health, as exemplified by Severe Acute Respiratory Syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV) and the newly emerged SARS-CoV-2, the causative agent of coronavirus disease 2019 (COVID-19). We describe herein the structure-guided optimization of a series of inhibitors of the coronavirus 3C-like protease (3CLpro), an enzyme essential for viral replication. The optimized compounds were effective against several human coronaviruses including MERS-CoV, SARS-CoV and SARS-CoV-2 in an enzyme assay and in cell-based assays using Huh-7 and Vero E6 cell lines. Two selected compounds showed antiviral effects against SARS-CoV-2 in cultured primary human airway epithelial cells. In a mouse model of MERS-CoV infection, administration of a lead compound one day after virus infection increased survival from 0 to 100% and reduced lung viral titers and lung histopathology. These results suggest that this series of compounds has the potential to be developed further as antiviral drugs against human coronaviruses. | ||
| + | |||
| + | 3C-like protease inhibitors block coronavirus replication in vitro and improve survival in MERS-CoV-infected mice.,Rathnayake AD, Zheng J, Kim Y, Perera KD, Mackin S, Meyerholz DK, Kashipathy MM, Battaile KP, Lovell S, Perlman S, Groutas WC, Chang KO Sci Transl Med. 2020 Aug 3. pii: scitranslmed.abc5332. doi:, 10.1126/scitranslmed.abc5332. PMID:32747425<ref>PMID:32747425</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 6w2a" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| + | [[Category: Cvhsa]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
| - | [[Category: Battaile | + | [[Category: Battaile, K P]] |
| - | [[Category: Chang | + | [[Category: Chang, K O]] |
| - | [[Category: Groutas | + | [[Category: Groutas, W C]] |
| - | [[Category: Kashipathy | + | [[Category: Kashipathy, M M]] |
| - | [[Category: Kim Y]] | + | [[Category: Kim, Y]] |
| - | [[Category: Lovell S]] | + | [[Category: Lovell, S]] |
| - | [[Category: Nguyen | + | [[Category: Nguyen, H N]] |
| - | [[Category: Rathnayake | + | [[Category: Rathnayake, A D]] |
| - | [[Category: Zheng J]] | + | [[Category: Zheng, J]] |
| + | [[Category: Hydrolase]] | ||
| + | [[Category: Hydrolase-hydrolase inhibitor complex]] | ||
| + | [[Category: Protease]] | ||
| + | [[Category: Sars 3cl protease inhhibitor]] | ||
| + | [[Category: Severe acute respiratory syndrome coronavirus]] | ||
Revision as of 06:38, 19 August 2020
1.65 A resolution structure of SARS-CoV 3CL protease in complex with inhibitor 7j
| |||||||||||
Categories: Cvhsa | Large Structures | Battaile, K P | Chang, K O | Groutas, W C | Kashipathy, M M | Kim, Y | Lovell, S | Nguyen, H N | Rathnayake, A D | Zheng, J | Hydrolase | Hydrolase-hydrolase inhibitor complex | Protease | Sars 3cl protease inhhibitor | Severe acute respiratory syndrome coronavirus
