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7k0g

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==1.85 A resolution structure of SARS-CoV 3CL protease in complex with deuterated GC376==
==1.85 A resolution structure of SARS-CoV 3CL protease in complex with deuterated GC376==
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<StructureSection load='7k0g' size='340' side='right'caption='[[7k0g]]' scene=''>
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<StructureSection load='7k0g' size='340' side='right'caption='[[7k0g]], [[Resolution|resolution]] 1.85&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7K0G OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7K0G FirstGlance]. <br>
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<table><tr><td colspan='2'>[[7k0g]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Hcov-sars Hcov-sars]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7K0G OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7K0G FirstGlance]. <br>
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</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=7k0g FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7k0g OCA], [https://pdbe.org/7k0g PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7k0g RCSB], [https://www.ebi.ac.uk/pdbsum/7k0g PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7k0g ProSAT]</span></td></tr>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=B1S:(1R,2S)-2-({N-[(benzyloxy)carbonyl]-L-leucyl}amino)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propane-1-sulfonic+acid'>B1S</scene>, <scene name='pdbligand=K36:(1S,2S)-2-({N-[(BENZYLOXY)CARBONYL]-L-LEUCYL}AMINO)-1-HYDROXY-3-[(3S)-2-OXOPYRROLIDIN-3-YL]PROPANE-1-SULFONIC+ACID'>K36</scene></td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">1a ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=694009 HCoV-SARS])</td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7k0g FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7k0g OCA], [https://pdbe.org/7k0g PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7k0g RCSB], [https://www.ebi.ac.uk/pdbsum/7k0g PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7k0g ProSAT]</span></td></tr>
</table>
</table>
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== Function ==
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[[https://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>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection continues to be a serious global public health threat. The 3C-like protease (3CLpro) is a virus protease encoded by SARS-CoV-2, which is essential for virus replication. We have previously reported a series of small-molecule 3CLpro inhibitors effective for inhibiting replication of human coronaviruses including SARS-CoV-2 in cell culture and in animal models. Here we generated a series of deuterated variants of a 3CLpro inhibitor, GC376, and evaluated the antiviral effect against SARS-CoV-2. The deuterated GC376 displayed potent inhibitory activity against SARS-CoV-2 in the enzyme- and the cell-based assays. The K18-hACE2 mice develop mild to lethal infection commensurate with SARS-CoV-2 challenge doses and were proposed as a model for efficacy testing of antiviral agents. We treated lethally infected mice with a deuterated derivative of GC376. Treatment of K18-hACE2 mice at 24 h postinfection with a derivative (compound 2) resulted in increased survival of mice compared to vehicle-treated mice. Lung virus titers were decreased, and histopathological changes were ameliorated in compound 2-treated mice compared to vehicle-treated mice. Structural investigation using high-resolution crystallography illuminated binding interactions of 3CLpro of SARS-CoV-2 and SARS-CoV with deuterated variants of GC376. Taken together, deuterated GC376 variants have excellent potential as antiviral agents against SARS-CoV-2.
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Postinfection treatment with a protease inhibitor increases survival of mice with a fatal SARS-CoV-2 infection.,Dampalla CS, Zheng J, Perera KD, Wong LR, Meyerholz DK, Nguyen HN, Kashipathy MM, Battaile KP, Lovell S, Kim Y, Perlman S, Groutas WC, Chang KO Proc Natl Acad Sci U S A. 2021 Jul 20;118(29). pii: 2101555118. doi:, 10.1073/pnas.2101555118. PMID:34210738<ref>PMID:34210738</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 7k0g" style="background-color:#fffaf0;"></div>
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== References ==
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<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Hcov-sars]]
[[Category: Large Structures]]
[[Category: Large Structures]]
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[[Category: Battaile KP]]
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[[Category: Battaile, K P]]
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[[Category: Chamandi SD]]
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[[Category: Chamandi, S D]]
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[[Category: Chang KO]]
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[[Category: Chang, K O]]
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[[Category: Groutas WC]]
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[[Category: Groutas, W C]]
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[[Category: Kashipathy MM]]
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[[Category: Kashipathy, M M]]
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[[Category: Kim Y]]
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[[Category: Kim, Y]]
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[[Category: Lovell S]]
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[[Category: Lovell, S]]
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[[Category: Nguyen HN]]
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[[Category: Nguyen, H N]]
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[[Category: Deuterated hydrolase inhibitor]]
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[[Category: Hydrolase]]
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[[Category: Hydrolase-hydrolase inhibitor complex]]
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[[Category: Protease]]
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[[Category: Sars 3cl protease inhhibitor]]
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[[Category: Severe acute respiratory syndrome coronavirus]]

Revision as of 10:09, 14 July 2021

1.85 A resolution structure of SARS-CoV 3CL protease in complex with deuterated GC376

PDB ID 7k0g

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