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==1.7A resolution structure of SARS-CoV-2 main protease (Mpro) in complex with broad-spectrum coronavirus protease inhibitor GC376== | ==1.7A resolution structure of SARS-CoV-2 main protease (Mpro) in complex with broad-spectrum coronavirus protease inhibitor GC376== | ||
<StructureSection load='7cb7' size='340' side='right'caption='[[7cb7]]' scene=''> | <StructureSection load='7cb7' size='340' side='right'caption='[[7cb7]], [[Resolution|resolution]] 1.69Å' 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=7CB7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7CB7 FirstGlance]. <br> | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7CB7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7CB7 FirstGlance]. <br> | ||
</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=7cb7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7cb7 OCA], [https://pdbe.org/7cb7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7cb7 RCSB], [https://www.ebi.ac.uk/pdbsum/7cb7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7cb7 ProSAT]</span></td></tr> | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.69Å</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>, <scene name='pdbligand=NA:SODIUM+ION'>NA</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=7cb7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7cb7 OCA], [https://pdbe.org/7cb7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7cb7 RCSB], [https://www.ebi.ac.uk/pdbsum/7cb7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7cb7 ProSAT]</span></td></tr> | |||
</table> | </table> | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or 2019 novel coronavirus (2019-nCoV), took tens of thousands of lives and caused tremendous economic losses. The main protease (M(pro)) of SARS-CoV-2 is a potential target for treatment of COVID-19 due to its critical role in maturation of viral proteins and subsequent viral replication. Conceptually and technically, targeting therapy against M(pro) is similar to target therapy to treat cancer. Previous studies show that GC376, a broad-spectrum dipeptidyl M(pro) inhibitor, efficiently blocks the proliferation of many animal and human coronaviruses including SARS-CoV, Middle East respiratory syndrome coronavirus (MERS-CoV), porcine epidemic diarrhea virus (PEDV), and feline infectious peritonitis virus (FIPV). Due to the conservation of structure and catalytic mechanism of coronavirus main protease, repurposition of GC376 against SARS-CoV-2 may be an effective way for the treatment of COVID-19 in humans. To validate this conjecture, the binding affinity and IC50 value of M(pro) with GC376 was determined by isothermal titration calorimetry (ITC) and fluorescence resonance energy transfer (FRET) assay, respectively. The results showed that GC376 binds to SARS-CoV-2 M(pro) tightly (KD = 1.6 muM) and efficiently inhibit its proteolytic activity (IC50 = 0.89 muM). We also elucidate the high-resolution structure of dimeric SARS-CoV-2 M(pro) in complex with GC376. The cocrystal structure showed that GC376 and the catalytic Cys145 of M(pro) covalently linked through forming a hemithioacetal group and releasing a sulfonic acid group. Because GC376 is already known as a broad-spectrum antiviral medication and successfully used in animal, it will be a suitable candidate for anti-COVID-19 treatment. | |||
Structural basis of SARS-CoV-2 main protease inhibition by a broad-spectrum anti-coronaviral drug.,Wang YC, Yang WH, Yang CS, Hou MH, Tsai CL, Chou YZ, Hung MC, Chen Y Am J Cancer Res. 2020 Aug 1;10(8):2535-2545. eCollection 2020. PMID:32905393<ref>PMID:32905393</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7cb7" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||