7aeh

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==SARS-CoV-2 main protease in a covalent complex with a pyridine derivative of ABT-957, compound 1==
==SARS-CoV-2 main protease in a covalent complex with a pyridine derivative of ABT-957, compound 1==
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<StructureSection load='7aeh' size='340' side='right'caption='[[7aeh]]' scene=''>
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<StructureSection load='7aeh' size='340' side='right'caption='[[7aeh]], [[Resolution|resolution]] 1.30&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=7AEH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7AEH FirstGlance]. <br>
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<table><tr><td colspan='2'>[[7aeh]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/2019-ncov 2019-ncov]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7AEH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7AEH 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=7aeh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7aeh OCA], [https://pdbe.org/7aeh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7aeh RCSB], [https://www.ebi.ac.uk/pdbsum/7aeh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7aeh 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=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=R8H:(2~{R})-5-oxidanylidene-~{N}-[(2~{R},3~{S})-3-oxidanyl-4-oxidanylidene-1-phenyl-4-(pyridin-2-ylmethylamino)butan-2-yl]-1-(phenylmethyl)pyrrolidine-2-carboxamide'>R8H</scene></td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">orf1ab ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=2697049 2019-nCoV])</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=7aeh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7aeh OCA], [https://pdbe.org/7aeh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7aeh RCSB], [https://www.ebi.ac.uk/pdbsum/7aeh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7aeh ProSAT]</span></td></tr>
</table>
</table>
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== Function ==
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[[https://www.uniprot.org/uniprot/A0A6B9VNL0_SARS2 A0A6B9VNL0_SARS2]] Forms a hexadecamer with nsp7 (8 subunits of each) that may participate in viral replication by acting as a primase. Alternatively, may synthesize substantially longer products than oligonucleotide primers.[ARBA:ARBA00002182] Forms a hexadecamer with nsp8 (8 subunits of each) that may participate in viral replication by acting as a primase. Alternatively, may synthesize substantially longer products than oligonucleotide primers.[ARBA:ARBA00003443] May participate in viral replication by acting as a ssRNA-binding protein.[ARBA:ARBA00002012] May play a role in the modulation of host cell survival signaling pathway by interacting with host PHB and PHB2. Indeed, these two proteins play a role in maintaining the functional integrity of the mitochondria and protecting cells from various stresses.[ARBA:ARBA00003115] Methyltransferase that mediates mRNA cap 2'-O-ribose methylation to the 5'-cap structure of viral mRNAs. N7-methyl guanosine cap is a prerequisite for binding of nsp16. Therefore plays an essential role in viral mRNAs cap methylation which is essential to evade immune system.[ARBA:ARBA00002840] Mn(2+)-dependent, uridylate-specific enzyme, which leaves 2'-3'-cyclic phosphates 5' to the cleaved bond.[ARBA:ARBA00002798] Multi-functional protein with a zinc-binding domain in N-terminus displaying RNA and DNA duplex-unwinding activities with 5' to 3' polarity. Activity of helicase is dependent on magnesium.[ARBA:ARBA00002960] Plays a pivotal role in viral transcription by stimulating both nsp14 3'-5' exoribonuclease and nsp16 2'-O-methyltransferase activities. Therefore plays an essential role in viral mRNAs cap methylation.[ARBA:ARBA00002697] Responsible for replication and transcription of the viral RNA genome.[ARBA:ARBA00003927]
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Effective agents to treat coronavirus infection are urgently required, not only to treat COVID-19, but to prepare for future outbreaks. Repurposed anti-virals such as remdesivir and human anti-inflammatories such as barcitinib have received emergency approval but their overall benefits remain unclear. Vaccines are the most promising prospect for COVID-19, but will need to be redeveloped for any future coronavirus outbreak. Protecting against future outbreaks requires the identification of targets that are conserved between coronavirus strains and amenable to drug discovery. Two such targets are the main protease (M(pro)) and the papain-like protease (PL(pro)) which are essential for the coronavirus replication cycle. We describe the discovery of two non-antiviral therapeutic agents, the caspase-1 inhibitor SDZ 224015 and Tarloxotinib that target M(pro) and PL(pro), respectively. These were identified through extensive experimental screens of the drug repurposing ReFRAME library of 12,000 therapeutic agents. The caspase-1 inhibitor SDZ 224015, was found to be a potent irreversible inhibitor of M(pro) (IC50 30 nM) while Tarloxotinib, a clinical stage epidermal growth factor receptor inhibitor, is a sub micromolar inhibitor of PL(pro) (IC50 300 nM, Ki 200 nM) and is the first reported PL(pro) inhibitor with drug-like properties. SDZ 224015 and Tarloxotinib have both undergone safety evaluation in humans and hence are candidates for COVID-19 clinical evaluation.
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Bispecific repurposed medicines targeting the viral and immunological arms of COVID-19.,Redhead MA, Owen CD, Brewitz L, Collette AH, Lukacik P, Strain-Damerell C, Robinson SW, Collins PM, Schafer P, Swindells M, Radoux CJ, Hopkins IN, Fearon D, Douangamath A, von Delft F, Malla TR, Vangeel L, Vercruysse T, Thibaut J, Leyssen P, Nguyen TT, Hull M, Tumber A, Hallett DJ, Schofield CJ, Stuart DI, Hopkins AL, Walsh MA Sci Rep. 2021 Jun 24;11(1):13208. doi: 10.1038/s41598-021-92416-4. PMID:34168183<ref>PMID:34168183</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 7aeh" style="background-color:#fffaf0;"></div>
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== References ==
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<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: 2019-ncov]]
[[Category: Large Structures]]
[[Category: Large Structures]]
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[[Category: Brewitz L]]
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[[Category: Brewitz, L]]
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[[Category: Collette A]]
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[[Category: Collette, A]]
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[[Category: Collins P]]
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[[Category: Collins, P]]
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[[Category: Douangamath A]]
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[[Category: Delft, F von]]
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[[Category: Fearon D]]
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[[Category: Douangamath, A]]
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[[Category: Hallet D]]
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[[Category: Fearon, D]]
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[[Category: Hopkins AL]]
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[[Category: Hallet, D]]
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[[Category: Hull H]]
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[[Category: Hopkins, A L]]
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[[Category: Lukacik P]]
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[[Category: Hull, H]]
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[[Category: Malla TR]]
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[[Category: Lukacik, P]]
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[[Category: Navratilova I]]
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[[Category: Malla, T R]]
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[[Category: Nugen T]]
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[[Category: Navratilova, I]]
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[[Category: Owen CD]]
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[[Category: Nugen, T]]
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[[Category: Radoux C]]
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[[Category: Owen, C D]]
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[[Category: Redhead MA]]
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[[Category: Radoux, C]]
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[[Category: Robinson C]]
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[[Category: Redhead, M A]]
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[[Category: Schofield CJ]]
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[[Category: Robinson, C]]
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[[Category: Strain-Damerell C]]
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[[Category: Schofield, C J]]
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[[Category: Stuart DI]]
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[[Category: Strain-Damerell, C]]
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[[Category: Tumber A]]
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[[Category: Stuart, D I]]
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[[Category: Walsh MA]]
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[[Category: Tumber, A]]
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[[Category: Von Delft F]]
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[[Category: Walsh, M A]]
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[[Category: Covid-19]]
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[[Category: Hydrolase]]
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[[Category: Inhibitor]]
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[[Category: Protease]]

Revision as of 06:15, 11 August 2021

SARS-CoV-2 main protease in a covalent complex with a pyridine derivative of ABT-957, compound 1

PDB ID 7aeh

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