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==Structure of SARS-CoV-2 Main Protease bound to AT7519==
==Structure of SARS-CoV-2 Main Protease bound to AT7519==
<StructureSection load='7aga' size='340' side='right'caption='[[7aga]], [[Resolution|resolution]] 1.68&Aring;' scene=''>
<StructureSection load='7aga' size='340' side='right'caption='[[7aga]]' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[7aga]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7AGA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7AGA FirstGlance]. <br>
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7AGA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7AGA FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=LZE:4-{[(2,6-DICHLOROPHENYL)CARBONYL]AMINO}-N-PIPERIDIN-4-YL-1H-PYRAZOLE-3-CARBOXAMIDE'>LZE</scene></td></tr>
</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=7aga FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7aga OCA], [https://pdbe.org/7aga PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7aga RCSB], [https://www.ebi.ac.uk/pdbsum/7aga PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7aga ProSAT]</span></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[7a1u|7a1u]], [[6yt8|6yt8]], [[6ynq|6ynq]], [[6yvf|6yvf]], [[6yz6|6yz6]], [[7af0|7af0]], [[7abu|7abu]], [[7adw|7adw]]</div></td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/SARS_coronavirus_main_proteinase SARS coronavirus main proteinase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.22.69 3.4.22.69] </span></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=7aga FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7aga OCA], [https://pdbe.org/7aga PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7aga RCSB], [https://www.ebi.ac.uk/pdbsum/7aga PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7aga ProSAT]</span></td></tr>
</table>
</table>
== Function ==
[[https://www.uniprot.org/uniprot/R1AB_SARS2 R1AB_SARS2]] Multifunctional protein involved in the transcription and replication of viral RNAs. Contains the proteinases responsible for the cleavages of the polyprotein.[UniProtKB:P0C6X7]  Inhibits host translation by interacting with the 40S ribosomal subunit. The nsp1-40S ribosome complex further induces an endonucleolytic cleavage near the 5'UTR of host mRNAs, targeting them for degradation. Viral mRNAs are not susceptible to nsp1-mediated endonucleolytic RNA cleavage thanks to the presence of a 5'-end leader sequence and are therefore protected from degradation. By suppressing host gene expression, nsp1 facilitates efficient viral gene expression in infected cells and evasion from host immune response.[UniProtKB:P0C6X7]  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.[UniProtKB:P0C6X7]  Responsible for the cleavages located at the N-terminus of the 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. Participates together with nsp4 in the assembly of virally-induced cytoplasmic double-membrane vesicles necessary for viral replication. Antagonizes innate immune induction of type I interferon by blocking the phosphorylation, dimerization and subsequent nuclear translocation of host IRF3. Prevents also host NF-kappa-B signaling.[UniProtKB:P0C6X7]  Participates in the assembly of virally-induced cytoplasmic double-membrane vesicles necessary for viral replication.[UniProtKB:P0C6X7]  Cleaves the C-terminus of replicase polyprotein at 11 sites. Recognizes substrates containing the core sequence [ILMVF]-Q-|-[SGACN] (PubMed:32198291). Also able to bind an ADP-ribose-1''-phosphate (ADRP).[UniProtKB:P0C6X7]<ref>PMID:32198291</ref>  Plays a role in the initial induction of autophagosomes from host reticulum endoplasmic. Later, limits the expansion of these phagosomes that are no longer able to deliver viral components to lysosomes.[UniProtKB:P0C6X7]  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.[UniProtKB:P0C6X7]  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.[UniProtKB:P0C6X7]  May participate in viral replication by acting as a ssRNA-binding protein.[UniProtKB:P0C6X7]  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.[UniProtKB:P0C6X7]  Responsible for replication and transcription of the viral RNA genome.[UniProtKB:P0C6X7]  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.[UniProtKB:P0C6X7]  Enzyme possessing two different activities: an exoribonuclease activity acting on both ssRNA and dsRNA in a 3' to 5' direction and a N7-guanine methyltransferase activity. Acts as a proofreading exoribonuclease for RNA replication, thereby lowering The sensitivity of the virus to RNA mutagens.[UniProtKB:P0C6X7]  Mn(2+)-dependent, uridylate-specific enzyme, which leaves 2'-3'-cyclic phosphates 5' to the cleaved bond.[UniProtKB:P0C6X7]  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.[UniProtKB:P0C6X7]
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The coronavirus disease (COVID-19) caused by SARS-CoV-2 is creating tremendous human suffering. To date, no effective drug is available to directly treat the disease. In a search for a drug against COVID-19, we have performed a high-throughput X-ray crystallographic screen of two repurposing drug libraries against the SARS-CoV-2 main protease (M(pro)), which is essential for viral replication. In contrast to commonly applied X-ray fragment screening experiments with molecules of low complexity, our screen tested already approved drugs and drugs in clinical trials. From the three-dimensional protein structures, we identified 37 compounds that bind to M(pro) In subsequent cell-based viral reduction assays, one peptidomimetic and six non-peptidic compounds showed antiviral activity at non-toxic concentrations. We identified two allosteric binding sites representing attractive targets for drug development against SARS-CoV-2.
X-ray screening identifies active site and allosteric inhibitors of SARS-CoV-2 main protease.,Gunther S, Reinke PYA, Fernandez-Garcia Y, Lieske J, Lane TJ, Ginn HM, Koua FHM, Ehrt C, Ewert W, Oberthuer D, Yefanov O, Meier S, Lorenzen K, Krichel B, Kopicki JD, Gelisio L, Brehm W, Dunkel I, Seychell B, Gieseler H, Norton-Baker B, Escudero-Perez B, Domaracky M, Saouane S, Tolstikova A, White TA, Hanle A, Groessler M, Fleckenstein H, Trost F, Galchenkova M, Gevorkov Y, Li C, Awel S, Peck A, Barthelmess M, Schluenzen F, Lourdu Xavier P, Werner N, Andaleeb H, Ullah N, Falke S, Srinivasan V, Franca BA, Schwinzer M, Brognaro H, Rogers C, Melo D, Zaitseva-Doyle JJ, Knoska J, Pena-Murillo GE, Mashhour AR, Hennicke V, Fischer P, Hakanpaa J, Meyer J, Gribbon P, Ellinger B, Kuzikov M, Wolf M, Beccari AR, Bourenkov G, von Stetten D, Pompidor G, Bento I, Panneerselvam S, Karpics I, Schneider TR, Garcia-Alai MM, Niebling S, Gunther C, Schmidt C, Schubert R, Han H, Boger J, Monteiro DCF, Zhang L, Sun X, Pletzer-Zelgert J, Wollenhaupt J, Feiler CG, Weiss MS, Schulz EC, Mehrabi P, Karnicar K, Usenik A, Loboda J, Tidow H, Chari A, Hilgenfeld R, Uetrecht C, Cox R, Zaliani A, Beck T, Rarey M, Gunther S, Turk D, Hinrichs W, Chapman HN, Pearson AR, Betzel C, Meents A Science. 2021 Apr 2. pii: science.abf7945. doi: 10.1126/science.abf7945. PMID:33811162<ref>PMID:33811162</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7aga" style="background-color:#fffaf0;"></div>


==See Also==
==See Also==
*[[Virus protease 3D structures|Virus protease 3D structures]]
*[[Virus protease 3D structures|Virus protease 3D structures]]
== References ==
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: SARS coronavirus main proteinase]]
[[Category: Alves Franca B]]
[[Category: Andaleeb, H]]
[[Category: Andaleeb H]]
[[Category: Awel, S]]
[[Category: Awel S]]
[[Category: Beck, T]]
[[Category: Beck T]]
[[Category: Betzel, C]]
[[Category: Betzel C]]
[[Category: Boger, J]]
[[Category: Boger J]]
[[Category: Brehm, W]]
[[Category: Brehm W]]
[[Category: Brognaro, H]]
[[Category: Brognaro H]]
[[Category: Chapman, H N]]
[[Category: Chapman HN]]
[[Category: Chari, A]]
[[Category: Chari A]]
[[Category: Domaracky, M]]
[[Category: Domaracky M]]
[[Category: Doyle, J J]]
[[Category: Doyle JJ]]
[[Category: Dunkel, I]]
[[Category: Dunkel I]]
[[Category: Ehrt, C]]
[[Category: Ehrt C]]
[[Category: Ellinger, B]]
[[Category: Ellinger B]]
[[Category: Esperanza, G Pena]]
[[Category: Falke S]]
[[Category: Falke, S]]
[[Category: Feiler C]]
[[Category: Feiler, C]]
[[Category: Fernandez Garcia Y]]
[[Category: Fischer, P]]
[[Category: Fischer P]]
[[Category: Fleckenstein, H]]
[[Category: Fleckenstein H]]
[[Category: Franca, B Alves]]
[[Category: Galchenkova M]]
[[Category: Galchenkova, M]]
[[Category: Gelisio L]]
[[Category: Garcia, Y Fernandez]]
[[Category: Gevorkov Y]]
[[Category: Gelisio, L]]
[[Category: Ginn H]]
[[Category: Gevorkov, Y]]
[[Category: Giseler H]]
[[Category: Ginn, H]]
[[Category: Gribbon P]]
[[Category: Giseler, H]]
[[Category: Groessler M]]
[[Category: Gribbon, P]]
[[Category: Guenther S]]
[[Category: Groessler, M]]
[[Category: Hakanpaeae J]]
[[Category: Guenther, S]]
[[Category: Han H]]
[[Category: Hakanpaeae, J]]
[[Category: Hennicke V]]
[[Category: Han, H]]
[[Category: Hilgenfeld R]]
[[Category: Hennicke, V]]
[[Category: Hinrichs W]]
[[Category: Hilgenfeld, R]]
[[Category: Knoska J]]
[[Category: Hinrichs, W]]
[[Category: Koua F]]
[[Category: Knoska, J]]
[[Category: Kuzikov M]]
[[Category: Koua, F]]
[[Category: Lane TJ]]
[[Category: Kuzikov, M]]
[[Category: Li C]]
[[Category: Lane, T J]]
[[Category: Lieske J]]
[[Category: Li, C]]
[[Category: Lorenzen K]]
[[Category: Lieske, J]]
[[Category: Meents A]]
[[Category: Lorenzen, K]]
[[Category: Mehrabi P]]
[[Category: Mashour, A Rahmani]]
[[Category: Meier S]]
[[Category: Meents, A]]
[[Category: Melo D]]
[[Category: Mehrabi, P]]
[[Category: Meyer J]]
[[Category: Meier, S]]
[[Category: Noei H]]
[[Category: Melo, D]]
[[Category: Norton-Baker B]]
[[Category: Meyer, J]]
[[Category: Oberthuer D]]
[[Category: Noei, H]]
[[Category: Paulraj LX]]
[[Category: Norton-Baker, B]]
[[Category: Pearson A]]
[[Category: Oberthuer, D]]
[[Category: Peck A]]
[[Category: Paulraj, L X]]
[[Category: Pena Esperanza G]]
[[Category: Pearson, A]]
[[Category: Perbandt M]]
[[Category: Peck, A]]
[[Category: Pletzer-Zelgert J]]
[[Category: Perbandt, M]]
[[Category: Rahmani Mashour A]]
[[Category: Pletzer-Zelgert, J]]
[[Category: Rarey M]]
[[Category: Rarey, M]]
[[Category: Reinke P]]
[[Category: Reinke, P]]
[[Category: Saouane S]]
[[Category: Saouane, S]]
[[Category: Schmidt C]]
[[Category: Schmidt, C]]
[[Category: Schubert R]]
[[Category: Schubert, R]]
[[Category: Schulz EC]]
[[Category: Schulz, E C]]
[[Category: Schwinzer M]]
[[Category: Schwinzer, M]]
[[Category: Seychell B]]
[[Category: Seychell, B]]
[[Category: Tidow H]]
[[Category: Tidow, H]]
[[Category: Tolstikova A]]
[[Category: Tolstikova, A]]
[[Category: Trost F]]
[[Category: Trost, F]]
[[Category: Turk D]]
[[Category: Turk, D]]
[[Category: Ullah N]]
[[Category: Ullah, N]]
[[Category: Weiss M]]
[[Category: Weiss, M]]
[[Category: Werner N]]
[[Category: Werner, N]]
[[Category: White TA]]
[[Category: White, T A]]
[[Category: Wolf M]]
[[Category: Wolf, M]]
[[Category: Wollenhaupt J]]
[[Category: Wollenhaupt, J]]
[[Category: Yefanov O]]
[[Category: Yefanov, O]]
[[Category: Zaliani A]]
[[Category: Zaliani, A]]
[[Category: Zhang L]]
[[Category: Zhang, L]]
[[Category: Covid-19]]
[[Category: Hydrolase]]
[[Category: Mpro]]
[[Category: Peptide binding protein]]
[[Category: Sars-cov-2]]
[[Category: Virus protease]]

Revision as of 14:00, 31 August 2022

Structure of SARS-CoV-2 Main Protease bound to AT7519Structure of SARS-CoV-2 Main Protease bound to AT7519

Structural highlights

Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

See Also

Drag the structure with the mouse to rotate

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA
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