7ju7 - Revision history

OCA at 15:11, 18 October 2023

OCA — Wed, 18 Oct 2023 15:11:34 GMT

←Older revision		Revision as of 15:11, 18 October 2023
Line 3:		Line 3:
	<StructureSection load='7ju7' size='340' side='right'caption='[[7ju7]], [[Resolution\|resolution]] 1.60Å' scene=''>		<StructureSection load='7ju7' size='340' side='right'caption='[[7ju7]], [[Resolution\|resolution]] 1.60Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[7ju7]] 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=7JU7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7JU7 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[7ju7]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Severe_acute_respiratory_syndrome_coronavirus_2 Severe acute respiratory syndrome coronavirus 2]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7JU7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7JU7 FirstGlance]. <br>
-	</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=G65:Masitinib'>G65</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>~~</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]] 1.6Å</td></tr>
-	<tr id='~~gene~~'><td class="sblockLbl"><b>[[~~Gene~~\|~~Gene~~:]]</b></td><td class="sblockDat">~~rep, 1a-1b ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode~~=~~Info&srchmode~~=~~5&id=2697049 2019-nCoV])</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=G65:Masitinib'>G65</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></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=7ju7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ju7 OCA], [https://pdbe.org/7ju7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ju7 RCSB], [https://www.ebi.ac.uk/pdbsum/7ju7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ju7 ProSAT]</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=7ju7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ju7 OCA], [https://pdbe.org/7ju7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ju7 RCSB], [https://www.ebi.ac.uk/pdbsum/7ju7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ju7 ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== 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]	+	[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;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 24:		Line 23:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: 2019-ncov]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: ~~SARS~~ coronavirus ~~main proteinase]]~~	+	[[Category: Severe acute respiratory syndrome coronavirus 2]]
-	~~[[Category: Structural genomic~~]]	+	[[Category: Jedrzejczak RP]]
-	[[Category: Jedrzejczak~~, R P~~]]	+	[[Category: Joachimiak A]]
-	[[Category: Joachimiak, A]]	+	[[Category: Maltseva NI]]
-	[[Category: Maltseva~~, N I~~]]	+	[[Category: Tan K]]
-	[[Category: Tan, K]]	+	[[Category: Welk LF]]
-	[[Category: Welk~~, L F]]~~	+
-	~~[[Category: Covid-19]]~~	+
-	~~[[Category: Csgid]]~~	+
-	~~[[Category: Hydrolase]]~~	+
-	~~[[Category: Main protease]]~~	+
-	~~[[Category: Masitinib]]~~	+
-	~~[[Category: Sars-cov-2~~]]	+

OCA at 06:30, 25 August 2021

OCA — Wed, 25 Aug 2021 06:30:38 GMT

←Older revision		Revision as of 06:30, 25 August 2021
Line 13:		Line 13:
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
-	There is an urgent need for ~~anti-viral~~ agents that treat SARS-CoV-2 infection. ~~The shortest path to clinical use is repurposing of drugs that have an established safety profile in humans. Here, we first~~ screened a library of ~~1,900~~ clinically safe drugs ~~for inhibiting replication of~~ OC43, a human beta-coronavirus that causes the common-cold ~~and is a relative of SARS-CoV-2~~, and ~~identified 108 effective drugs. We further~~ evaluated the top 26 hits ~~and determined their ability to inhibit~~ SARS-CoV-2~~, as well as other pathogenic RNA viruses~~. ~~20 of the 26~~ drugs significantly inhibited ~~SARS-CoV-2~~ replication in human ~~lung~~ cells ~~(A549 epithelial cell line), with EC50 values ranging from 0~~.~~1 to 8 micromolar. We investigated the mechanism~~ of ~~action for~~ these ~~and found that masitinib, a drug originally developed as a tyrosine-kinase inhibitor for cancer treatment, strongly~~ inhibited the activity of the SARS-CoV-2 main protease 3CLpro. X-ray crystallography ~~revealed~~ that masitinib ~~directly binds to the active site~~ of 3CLpro, ~~thereby blocking its enzymatic activity~~. ~~Mastinib~~ also ~~inhibited the related viral protease~~ of ~~picornaviruses and blocked picornaviruses replication~~. ~~Thus~~, ~~our results show that masitinib has broad anti-viral activity against two distinct beta-coronaviruses~~ and ~~multiple picornaviruses that cause human disease and is a strong candidate for clinical trials to treat SARS-CoV-2 infection~~.	+	There is an urgent need for antiviral agents that treat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We screened a library of 1900 clinically safe drugs against OC43, a human beta coronavirus that causes the common cold, and evaluated the top hits against SARS-CoV-2. Twenty drugs significantly inhibited replication of both viruses in cultured human cells. Eight of these drugs inhibited the activity of the SARS-CoV-2 main protease, 3CLpro, with the most potent being masitinib, an orally bioavailable tyrosine kinase inhibitor. X-ray crystallography and biochemistry show that masitinib acts as a competitive inhibitor of 3CLpro. Mice infected with SARS-CoV-2 and then treated with masitinib showed >200-fold reduction in viral titers in the lungs and nose, as well as reduced lung inflammation. Masitinib was also effective in vitro against all tested variants of concern (B.1.1.7, B.1.351, and P.1).

-	~~Drug repurposing screen identifies masitinib as~~ a ~~3CLpro~~ inhibitor that blocks replication of SARS-CoV-2 ~~in vitro~~.,Drayman N, Jones KA, Azizi SA, Froggatt HM, Tan K, Maltseva NI, Chen S, Nicolaescu V, Dvorkin S, Furlong K, Kathayat RS, Firpo MR, Mastrodomenico V, Bruce EA, Schmidt MM, Jedrzejczak R, Munoz-Alia MA, Schuster B, Nair V, Botten JW, Brooke CB, Baker SC, Mounce BC, Heaton NS, Dickinson BC, ~~Jaochimiak~~ A, Randall G, Tay S ~~bioRxiv~~. ~~2020 Sep 1~~. doi: 10.~~1101~~/~~2020~~.08.~~31.274639~~. PMID:~~32908976~~<ref>PMID:~~32908976~~</ref>	+	Masitinib is a broad coronavirus 3CL inhibitor that blocks replication of SARS-CoV-2.,Drayman N, DeMarco JK, Jones KA, Azizi SA, Froggatt HM, Tan K, Maltseva NI, Chen S, Nicolaescu V, Dvorkin S, Furlong K, Kathayat RS, Firpo MR, Mastrodomenico V, Bruce EA, Schmidt MM, Jedrzejczak R, Munoz-Alia MA, Schuster B, Nair V, Han KY, O'Brien A, Tomatsidou A, Meyer B, Vignuzzi M, Missiakas D, Botten JW, Brooke CB, Lee H, Baker SC, Mounce BC, Heaton NS, Severson WE, Palmer KE, Dickinson BC, Joachimiak A, Randall G, Tay S Science. 2021 Aug 20;373(6557):931-936. doi: 10.1126/science.abg5827. Epub 2021, Jul 20. PMID:34285133<ref>PMID:34285133</ref>

	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>		From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>

OCA at 10:49, 28 July 2021

OCA — Wed, 28 Jul 2021 10:49:01 GMT

←Older revision		Revision as of 10:49, 28 July 2021
Line 1:		Line 1:

	==The crystal structure of SARS-CoV-2 Main Protease in complex with masitinib==		==The crystal structure of SARS-CoV-2 Main Protease in complex with masitinib==
-	<StructureSection load='7ju7' size='340' side='right'caption='[[7ju7]]' scene=''>	+	<StructureSection load='7ju7' size='340' side='right'caption='[[7ju7]], [[Resolution\|resolution]] 1.60Å' 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=7JU7 OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://proteopedia.org/fgij/fg.htm?mol=7JU7 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[7ju7]] 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=7JU7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7JU7 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=7ju7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ju7 OCA], [~~http~~://pdbe.org/7ju7 PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=7ju7 RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/7ju7 PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=7ju7 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=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=G65:Masitinib'>G65</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">rep, 1a-1b ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=2697049 2019-nCoV])</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=7ju7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ju7 OCA], [https://pdbe.org/7ju7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ju7 RCSB], [https://www.ebi.ac.uk/pdbsum/7ju7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ju7 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 ==
		+	There is an urgent need for anti-viral agents that treat SARS-CoV-2 infection. The shortest path to clinical use is repurposing of drugs that have an established safety profile in humans. Here, we first screened a library of 1,900 clinically safe drugs for inhibiting replication of OC43, a human beta-coronavirus that causes the common-cold and is a relative of SARS-CoV-2, and identified 108 effective drugs. We further evaluated the top 26 hits and determined their ability to inhibit SARS-CoV-2, as well as other pathogenic RNA viruses. 20 of the 26 drugs significantly inhibited SARS-CoV-2 replication in human lung cells (A549 epithelial cell line), with EC50 values ranging from 0.1 to 8 micromolar. We investigated the mechanism of action for these and found that masitinib, a drug originally developed as a tyrosine-kinase inhibitor for cancer treatment, strongly inhibited the activity of the SARS-CoV-2 main protease 3CLpro. X-ray crystallography revealed that masitinib directly binds to the active site of 3CLpro, thereby blocking its enzymatic activity. Mastinib also inhibited the related viral protease of picornaviruses and blocked picornaviruses replication. Thus, our results show that masitinib has broad anti-viral activity against two distinct beta-coronaviruses and multiple picornaviruses that cause human disease and is a strong candidate for clinical trials to treat SARS-CoV-2 infection.
		+
		+	Drug repurposing screen identifies masitinib as a 3CLpro inhibitor that blocks replication of SARS-CoV-2 in vitro.,Drayman N, Jones KA, Azizi SA, Froggatt HM, Tan K, Maltseva NI, Chen S, Nicolaescu V, Dvorkin S, Furlong K, Kathayat RS, Firpo MR, Mastrodomenico V, Bruce EA, Schmidt MM, Jedrzejczak R, Munoz-Alia MA, Schuster B, Nair V, Botten JW, Brooke CB, Baker SC, Mounce BC, Heaton NS, Dickinson BC, Jaochimiak A, Randall G, Tay S bioRxiv. 2020 Sep 1. doi: 10.1101/2020.08.31.274639. PMID:32908976<ref>PMID:32908976</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 7ju7" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: 2019-ncov]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Jedrzejczak RP]]	+	[[Category: SARS coronavirus main proteinase]]
-	[[Category: Joachimiak A]]	+	[[Category: Structural genomic]]
-	[[Category: Maltseva NI]]	+	[[Category: Jedrzejczak, R P]]
-	[[Category: Tan K]]	+	[[Category: Joachimiak, A]]
-	[[Category: Welk LF]]	+	[[Category: Maltseva, N I]]
		+	[[Category: Tan, K]]
		+	[[Category: Welk, L F]]
		+	[[Category: Covid-19]]
		+	[[Category: Csgid]]
		+	[[Category: Hydrolase]]
		+	[[Category: Main protease]]
		+	[[Category: Masitinib]]
		+	[[Category: Sars-cov-2]]

OCA at 09:38, 9 September 2020

OCA — Wed, 09 Sep 2020 09:38:40 GMT

←Older revision		Revision as of 09:38, 9 September 2020
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry 7ju7 is ON HOLD~~	+	==The crystal structure of SARS-CoV-2 Main Protease in complex with masitinib==
-		+	<StructureSection load='7ju7' size='340' side='right'caption='[[7ju7]]' scene=''>
-	~~Authors: Tan, K., Maltseva, N.I., Welk, L.F., Jedrzejczak, R.P., Joachimiak, A., Center for Structural Genomics of Infectious Diseases (CSGID)~~	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7JU7 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=7JU7 FirstGlance]. <br>
-	~~Description:~~ The crystal structure of SARS-CoV-2 Main Protease in complex with masitinib	+	</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=7ju7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ju7 OCA], [http://pdbe.org/7ju7 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=7ju7 RCSB], [http://www.ebi.ac.uk/pdbsum/7ju7 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=7ju7 ProSAT]</span></td></tr>
-	[[~~Category~~: ~~Unreleased Structures~~]]	+	</table>
-	[[~~Category~~: ~~Joachimiak~~, A]]	+	__TOC__
-	[[Category: ~~Tan, K~~]]	+	</StructureSection>
-	[[Category: Jedrzejczak~~, R.P~~]]	+	[[Category: Large Structures]]
-	[[Category: Maltseva~~, N.I~~]]	+	[[Category: Jedrzejczak RP]]
-	[[Category: ~~Welk, L.F~~]]	+	[[Category: Joachimiak A]]
-	[[Category: ~~Center For Structural Genomics Of Infectious Diseases (Csgid)~~]]	+	[[Category: Maltseva NI]]
		+	[[Category: Tan K]]
		+	[[Category: Welk LF]]

OCA: Protected "7ju7" [edit=sysop:move=sysop]

OCA — Wed, 26 Aug 2020 09:41:52 GMT

Protected "7ju7" [edit=sysop:move=sysop]

←Older revision

Revision as of 09:41, 26 August 2020

OCA: New page: '''Unreleased structure''' The entry 7ju7 is ON HOLD Authors: Tan, K., Maltseva, N.I., Welk, L.F., Jedrzejczak, R.P., Joachimiak, A., Center for Structural Genomics of Infectious Diseas...

OCA — Wed, 26 Aug 2020 09:41:50 GMT

New page: '''Unreleased structure''' The entry 7ju7 is ON HOLD Authors: Tan, K., Maltseva, N.I., Welk, L.F., Jedrzejczak, R.P., Joachimiak, A., Center for Structural Genomics of Infectious Diseas...

New page

'''Unreleased structure'''

The entry 7ju7 is ON HOLD

Authors: Tan, K., Maltseva, N.I., Welk, L.F., Jedrzejczak, R.P., Joachimiak, A., Center for Structural Genomics of Infectious Diseases (CSGID)

Description: The crystal structure of SARS-CoV-2 Main Protease in complex with masitinib
[[Category: Unreleased Structures]]
[[Category: Joachimiak, A]]
[[Category: Tan, K]]
[[Category: Jedrzejczak, R.P]]
[[Category: Maltseva, N.I]]
[[Category: Welk, L.F]]
[[Category: Center For Structural Genomics Of Infectious Diseases (Csgid)]]