7mhm - Revision history

OCA at 09:21, 25 October 2023

2023-10-25T09:21:41Z

←Older revision		Revision as of 09:21, 25 October 2023
Line 4:		Line 4:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[7mhm]] 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=7MHM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7MHM FirstGlance]. <br>		<table><tr><td colspan='2'>[[7mhm]] 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=7MHM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7MHM 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=ZN:ZINC+ION'>ZN</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]] 1.5302Å</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=ZN:ZINC+ION'>ZN</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=7mhm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7mhm OCA], [https://pdbe.org/7mhm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7mhm RCSB], [https://www.ebi.ac.uk/pdbsum/7mhm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7mhm 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=7mhm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7mhm OCA], [https://pdbe.org/7mhm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7mhm RCSB], [https://www.ebi.ac.uk/pdbsum/7mhm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7mhm ProSAT]</span></td></tr>
	</table>		</table>

OCA at 07:42, 8 March 2023

2023-03-08T07:42:06Z

←Older revision		Revision as of 07:42, 8 March 2023
Line 8:		Line 8:
	</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]
	== References ==		== References ==
	<references/>		<references/>

OCA at 16:47, 7 September 2022

2022-09-07T16:47:08Z

←Older revision		Revision as of 16:47, 7 September 2022
Line 3:		Line 3:
	<StructureSection load='7mhm' size='340' side='right'caption='[[7mhm]], [[Resolution\|resolution]] 1.53Å' scene=''>		<StructureSection load='7mhm' size='340' side='right'caption='[[7mhm]], [[Resolution\|resolution]] 1.53Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[7mhm]] 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=7MHM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7MHM FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[7mhm]] 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=7MHM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7MHM 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=ZN:ZINC+ION'>ZN</scene></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=ZN:ZINC+ION'>ZN</scene></td></tr>
-	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[7mhl\|7mhl]], [[7mhn\|7mhn]], [[7mho\|7mho]], [[7mhp\|7mhp]], [[7mhq\|7mhq]], [[7mhf\|7mhf]], [[7mhg\|7mhg]], [[7mhh\|7mhh]], [[7mhi\|7mhi]], [[7mhj\|7mhj]], [[7mhk\|7mhk]]</div></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=7mhm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7mhm OCA], [https://pdbe.org/7mhm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7mhm RCSB], [https://www.ebi.ac.uk/pdbsum/7mhm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7mhm 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=7mhm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7mhm OCA], [https://pdbe.org/7mhm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7mhm RCSB], [https://www.ebi.ac.uk/pdbsum/7mhm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7mhm 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;">~~	+
-	~~== Publication Abstract from PubMed ==~~	+
-	The COVID-19 pandemic, instigated by the SARS-CoV-2 coronavirus, continues to plague the globe. The SARS-CoV-2 main protease, or M (pro) , is a promising target for development of novel antiviral therapeutics. Previous X-ray crystal structures of M (pro) were obtained at cryogenic temperature or room temperature only. Here we report a series of high-resolution crystal structures of unliganded M (pro) across multiple temperatures from cryogenic to physiological, and another at high humidity. We interrogate these datasets with parsimonious multiconformer models, multi-copy ensemble models, and isomorphous difference density maps. Our analysis reveals a temperature-dependent conformational landscape for M (pro) , including a mobile water interleaved between the catalytic dyad, mercurial conformational heterogeneity in a key substrate-binding loop, and a far-reaching intramolecular network bridging the active site and dimer interface. Our results may inspire new strategies for antiviral drug development to counter-punch COVID-19 and combat future coronavirus pandemics.	+
-		+
-	The temperature-dependent conformational ensemble of SARS-CoV-2 main protease (M (pro) ).,Ebrahim A, Riley BT, Kumaran D, Andi B, Fuchs MR, McSweeney S, Keedy DA bioRxiv. 2021 May 3. doi: 10.1101/2021.05.03.437411. PMID:33972941<ref>PMID:33972941</ref>	+
-		+
-	~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~	+
-	~~</div>~~	+
-	~~<div class="pdbe-citations 7mhm" style="background-color:#fffaf0;"></div>~~	+
	== References ==		== References ==
	<references/>		<references/>
	__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: Andi, B]]	+	[[Category: Andi B]]
-	[[Category: Ebrahim, A]]	+	[[Category: Ebrahim A]]
-	[[Category: Fuchs~~, M R~~]]	+	[[Category: Fuchs MR]]
-	[[Category: Keedy~~, D A~~]]	+	[[Category: Keedy DA]]
-	[[Category: Kumaran, D]]	+	[[Category: Kumaran D]]
-	[[Category: McSweeney, S]]	+	[[Category: McSweeney S]]
-	[[Category: Riley~~, B T]]~~	+	[[Category: Riley BT]]
-	~~[[Category: Coronavirus]]~~	+
-	~~[[Category: Ensemble refinement]]~~	+
-	~~[[Category: Hydrolase]]~~	+
-	~~[[Category: Main protease]]~~	+
-	~~[[Category: Mpro]]~~	+
-	~~[[Category: Multitemperature]]~~	+
-	~~[[Category: Sars-cov-2]]~~	+
-	~~[[Category: Temperature]]~~	+
-	~~[[Category: Temperature series~~]]	+

OCA at 10:33, 6 April 2022

2022-04-06T10:33:36Z

←Older revision		Revision as of 10:33, 6 April 2022
Line 1:		Line 1:

-	==Ensemble refinement structure of ~~apo/unliganded~~ SARS-CoV-2 main protease (Mpro) at 240 K==	+	==Ensemble refinement structure of SARS-CoV-2 main protease (Mpro) at 240 K==
	<StructureSection load='7mhm' size='340' side='right'caption='[[7mhm]], [[Resolution\|resolution]] 1.53Å' scene=''>		<StructureSection load='7mhm' size='340' side='right'caption='[[7mhm]], [[Resolution\|resolution]] 1.53Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[7mhm]] 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=7MHM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7MHM FirstGlance]. <br>		<table><tr><td colspan='2'>[[7mhm]] 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=7MHM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7MHM 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></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=ZN:ZINC+ION'>ZN</scene></td></tr>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[7mhl\|7mhl]], [[7mhn\|7mhn]], [[7mho\|7mho]], [[7mhp\|7mhp]], [[7mhq\|7mhq]], [[7mhf\|7mhf]], [[7mhg\|7mhg]], [[7mhh\|7mhh]], [[7mhi\|7mhi]], [[7mhj\|7mhj]], [[7mhk\|7mhk]]</div></td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[7mhl\|7mhl]], [[7mhn\|7mhn]], [[7mho\|7mho]], [[7mhp\|7mhp]], [[7mhq\|7mhq]], [[7mhf\|7mhf]], [[7mhg\|7mhg]], [[7mhh\|7mhh]], [[7mhi\|7mhi]], [[7mhj\|7mhj]], [[7mhk\|7mhk]]</div></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='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>
Line 35:		Line 35:
	[[Category: McSweeney, S]]		[[Category: McSweeney, S]]
	[[Category: Riley, B T]]		[[Category: Riley, B T]]
-	[[Category: Apo]]
	[[Category: Coronavirus]]		[[Category: Coronavirus]]
	[[Category: Ensemble refinement]]		[[Category: Ensemble refinement]]
Line 45:		Line 44:
	[[Category: Temperature]]		[[Category: Temperature]]
	[[Category: Temperature series]]		[[Category: Temperature series]]
-	[[Category: Unliganded]]

OCA at 09:31, 26 May 2021

2021-05-26T09:31:42Z

←Older revision		Revision as of 09:31, 26 May 2021
Line 1:		Line 1:

	==Ensemble refinement structure of apo/unliganded SARS-CoV-2 main protease (Mpro) at 240 K==		==Ensemble refinement structure of apo/unliganded SARS-CoV-2 main protease (Mpro) at 240 K==
-	<StructureSection load='7mhm' size='340' side='right'caption='[[7mhm]]' scene=''>	+	<StructureSection load='7mhm' size='340' side='right'caption='[[7mhm]], [[Resolution\|resolution]] 1.53Å' 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=7MHM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7MHM FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[7mhm]] 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=7MHM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7MHM 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=7mhm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7mhm OCA], [https://pdbe.org/7mhm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7mhm RCSB], [https://www.ebi.ac.uk/pdbsum/7mhm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7mhm 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></td></tr>
		+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[7mhl\|7mhl]], [[7mhn\|7mhn]], [[7mho\|7mho]], [[7mhp\|7mhp]], [[7mhq\|7mhq]], [[7mhf\|7mhf]], [[7mhg\|7mhg]], [[7mhh\|7mhh]], [[7mhi\|7mhi]], [[7mhj\|7mhj]], [[7mhk\|7mhk]]</div></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=7mhm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7mhm OCA], [https://pdbe.org/7mhm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7mhm RCSB], [https://www.ebi.ac.uk/pdbsum/7mhm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7mhm 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 COVID-19 pandemic, instigated by the SARS-CoV-2 coronavirus, continues to plague the globe. The SARS-CoV-2 main protease, or M (pro) , is a promising target for development of novel antiviral therapeutics. Previous X-ray crystal structures of M (pro) were obtained at cryogenic temperature or room temperature only. Here we report a series of high-resolution crystal structures of unliganded M (pro) across multiple temperatures from cryogenic to physiological, and another at high humidity. We interrogate these datasets with parsimonious multiconformer models, multi-copy ensemble models, and isomorphous difference density maps. Our analysis reveals a temperature-dependent conformational landscape for M (pro) , including a mobile water interleaved between the catalytic dyad, mercurial conformational heterogeneity in a key substrate-binding loop, and a far-reaching intramolecular network bridging the active site and dimer interface. Our results may inspire new strategies for antiviral drug development to counter-punch COVID-19 and combat future coronavirus pandemics.
		+
		+	The temperature-dependent conformational ensemble of SARS-CoV-2 main protease (M (pro) ).,Ebrahim A, Riley BT, Kumaran D, Andi B, Fuchs MR, McSweeney S, Keedy DA bioRxiv. 2021 May 3. doi: 10.1101/2021.05.03.437411. PMID:33972941<ref>PMID:33972941</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 7mhm" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: 2019-ncov]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Andi B]]	+	[[Category: SARS coronavirus main proteinase]]
-	[[Category: Ebrahim A]]	+	[[Category: Andi, B]]
-	[[Category: Fuchs MR]]	+	[[Category: Ebrahim, A]]
-	[[Category: Keedy DA]]	+	[[Category: Fuchs, M R]]
-	[[Category: Kumaran D]]	+	[[Category: Keedy, D A]]
-	[[Category: McSweeney S]]	+	[[Category: Kumaran, D]]
-	[[Category: Riley BT]]	+	[[Category: McSweeney, S]]
		+	[[Category: Riley, B T]]
		+	[[Category: Apo]]
		+	[[Category: Coronavirus]]
		+	[[Category: Ensemble refinement]]
		+	[[Category: Hydrolase]]
		+	[[Category: Main protease]]
		+	[[Category: Mpro]]
		+	[[Category: Multitemperature]]
		+	[[Category: Sars-cov-2]]
		+	[[Category: Temperature]]
		+	[[Category: Temperature series]]
		+	[[Category: Unliganded]]

OCA at 09:22, 12 May 2021

2021-05-12T09:22:35Z

←Older revision		Revision as of 09:22, 12 May 2021
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 7mhm ~~is ON HOLD until Paper Publication~~	+	==Ensemble refinement structure of apo/unliganded SARS-CoV-2 main protease (Mpro) at 240 K==
-		+	<StructureSection load='7mhm' size='340' side='right'caption='[[7mhm]]' scene=''>
-	~~Authors~~: ~~Ebrahim, A~~.~~, Riley, B~~.T., ~~Kumaran, D~~., ~~Andi, B~~., ~~Fuchs, M~~.R., ~~McSweeney, S~~., ~~Keedy, D~~.A.	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7MHM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7MHM FirstGlance]. <br>
-	~~Description: Ensemble refinement structure of apo~~/~~unliganded SARS-CoV-2 main protease (Mpro) at 240 K~~	+	</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=7mhm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7mhm OCA], [https://pdbe.org/7mhm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7mhm RCSB], [https://www.ebi.ac.uk/pdbsum/7mhm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7mhm ProSAT]</span></td></tr>
-	[[Category: ~~Unreleased~~ Structures]]	+	</table>
-	[[Category: ~~Mcsweeney, S~~]]	+	__TOC__
-	[[Category: Ebrahim, A]]	+	</StructureSection>
-	[[Category: Fuchs~~, M.R~~]]	+	[[Category: Large Structures]]
-	[[Category: ~~Kumaran, D~~]]	+	[[Category: Andi B]]
-	[[Category: ~~Andi, B~~]]	+	[[Category: Ebrahim A]]
-	[[Category: ~~Keedy, D.A~~]]	+	[[Category: Fuchs MR]]
-	[[Category: Riley~~, B.T~~]]	+	[[Category: Keedy DA]]
		+	[[Category: Kumaran D]]
		+	[[Category: McSweeney S]]
		+	[[Category: Riley BT]]

OCA at 04:18, 28 April 2021

2021-04-28T04:18:19Z

←Older revision		Revision as of 04:18, 28 April 2021
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 7mhm is ON HOLD	+	The entry 7mhm is ON HOLD until Paper Publication

	Authors: Ebrahim, A., Riley, B.T., Kumaran, D., Andi, B., Fuchs, M.R., McSweeney, S., Keedy, D.A.		Authors: Ebrahim, A., Riley, B.T., Kumaran, D., Andi, B., Fuchs, M.R., McSweeney, S., Keedy, D.A.
Line 7:		Line 7:
	Description: Ensemble refinement structure of apo/unliganded SARS-CoV-2 main protease (Mpro) at 240 K		Description: Ensemble refinement structure of apo/unliganded SARS-CoV-2 main protease (Mpro) at 240 K
	[[Category: Unreleased Structures]]		[[Category: Unreleased Structures]]
-	[[Category: Andi, B]]
	[[Category: Mcsweeney, S]]		[[Category: Mcsweeney, S]]
	[[Category: Ebrahim, A]]		[[Category: Ebrahim, A]]
	[[Category: Fuchs, M.R]]		[[Category: Fuchs, M.R]]
	[[Category: Kumaran, D]]		[[Category: Kumaran, D]]
		+	[[Category: Andi, B]]
	[[Category: Keedy, D.A]]		[[Category: Keedy, D.A]]
	[[Category: Riley, B.T]]		[[Category: Riley, B.T]]

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

2021-04-21T06:26:56Z

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

←Older revision

Revision as of 06:26, 21 April 2021

OCA: New page: '''Unreleased structure''' The entry 7mhm is ON HOLD Authors: Ebrahim, A., Riley, B.T., Kumaran, D., Andi, B., Fuchs, M.R., McSweeney, S., Keedy, D.A. Description: Ensemble refinement ...

2021-04-21T06:26:55Z

New page: '''Unreleased structure''' The entry 7mhm is ON HOLD Authors: Ebrahim, A., Riley, B.T., Kumaran, D., Andi, B., Fuchs, M.R., McSweeney, S., Keedy, D.A. Description: Ensemble refinement ...

New page

'''Unreleased structure'''

The entry 7mhm is ON HOLD

Authors: Ebrahim, A., Riley, B.T., Kumaran, D., Andi, B., Fuchs, M.R., McSweeney, S., Keedy, D.A.

Description: Ensemble refinement structure of apo/unliganded SARS-CoV-2 main protease (Mpro) at 240 K
[[Category: Unreleased Structures]]
[[Category: Andi, B]]
[[Category: Mcsweeney, S]]
[[Category: Ebrahim, A]]
[[Category: Fuchs, M.R]]
[[Category: Kumaran, D]]
[[Category: Keedy, D.A]]
[[Category: Riley, B.T]]