6xho - Revision history

OCA at 14:52, 18 October 2023

OCA — Wed, 18 Oct 2023 14:52:36 GMT

←Older revision		Revision as of 14:52, 18 October 2023
Line 3:		Line 3:
	<StructureSection load='6xho' size='340' side='right'caption='[[6xho]], [[Resolution\|resolution]] 1.45Å' scene=''>		<StructureSection load='6xho' size='340' side='right'caption='[[6xho]], [[Resolution\|resolution]] 1.45Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6xho]] is a 2 chain structure with sequence from [~~http~~://en.wikipedia.org/wiki/~~Hcov~~-~~sars Hcov~~-~~sars~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6XHO OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://proteopedia.org/fgij/fg.htm?mol=6XHO FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6xho]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Severe_acute_respiratory_syndrome-related_coronavirus Severe acute respiratory syndrome-related coronavirus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6XHO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6XHO FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=V34:ethyl+(2E,4S)-4-{[N-(4-methoxy-1H-indole-2-carbonyl)-L-leucyl]amino}-5-[(3S)-2-oxopyrrolidin-3-yl]pent-2-enoate'>V34</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]] 1.446Å</td></tr>
-	~~<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">1a ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=694009 HCoV-SARS])</td></tr>~~	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=V34:ethyl+(2E,4S)-4-{[N-(4-methoxy-1H-indole-2-carbonyl)-L-leucyl]amino}-5-[(3S)-2-oxopyrrolidin-3-yl]pent-2-enoate'>V34</scene></td></tr>
-	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/SARS_coronavirus_main_proteinase SARS coronavirus main proteinase], with EC number [http://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=6xho FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6xho OCA], [https://pdbe.org/6xho PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6xho RCSB], [https://www.ebi.ac.uk/pdbsum/6xho PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6xho ProSAT]</span></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=6xho FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6xho OCA], [~~http~~://pdbe.org/6xho PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=6xho RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/6xho PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=6xho ProSAT]</span></td></tr>	+
	</table>		</table>
	== Function ==		== Function ==
-	[~~[http~~://www.uniprot.org/uniprot/~~R1A_CVHSA R1A_CVHSA]~~] The ~~papain~~-~~like proteinase (PL~~-~~PRO~~) ~~is responsible~~ for the cleavages located at the N-terminus of 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. Antagonizes innate immune induction of type I interferon by blocking the phosphorylation, dimerization and subsequent nuclear translocation of host ~~IRF~~-3.<ref>PMID:~~17024178~~</ref> <ref>PMID:17692280</ref> <ref>PMID:19369340</ref> ~~The main proteinase 3CL~~-~~PRO is responsible~~ for ~~the majority of cleavages as it cleaves~~ the C-terminus of replicase polyprotein at 11 sites. Recognizes substrates containing the core sequence [ILMVF]-Q-\|-[SGACN]~~. Inhibited by the substrate-analog Cbz-Val-Asn-Ser-Thr-Leu-Gln-CMK (By similarity)~~. Also ~~contains~~ an ADP-ribose-1''-phosphate (ADRP)~~-binding function~~.<ref>PMID:~~17024178~~</ref> <ref>PMID:~~17692280~~</ref> <ref>PMID:~~19369340~~</ref> ~~Nsp7-nsp8~~ hexadecamer may ~~possibly confer processivity to the polymerase, maybe by binding to dsRNA or~~ by ~~producing~~ primers ~~utilized by the latter~~.<ref>PMID:~~17024178~~</ref> <ref>PMID:~~17692280</ref> <ref>PMID:19369340~~</ref> ~~Nsp9 is~~ a ssRNA-binding protein.<ref>PMID:~~17024178~~</ref> <ref>PMID:~~17692280~~</ref> ~~<ref>PMID:19369340</ref>~~	+	[https://www.uniprot.org/uniprot/R1A_SARS R1A_SARS] Multifunctional protein involved in the transcription and replication of viral RNAs. Contains the proteinases responsible for the cleavages of the polyprotein. 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 (PubMed:23035226). May disrupt nuclear pore function by binding and displacing host NUP93 (PubMed:30943371).<ref>PMID:23035226</ref> <ref>PMID:30943371</ref> 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.<ref>PMID:19640993</ref> 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 (PubMed:17692280). Plays a role in host membrane rearrangement that leads to creation of cytoplasmic double-membrane vesicles (DMV) necessary for viral replication. Nsp3, nsp4 and nsp6 together are sufficient to form DMV (PubMed:24410069). Antagonizes innate immune induction of type I interferon by blocking the phosphorylation, dimerization and subsequent nuclear translocation of host IRF3 (PubMed:19369340, PubMed:24622840). Prevents also host NF-kappa-B signaling.<ref>PMID:16271890</ref> <ref>PMID:17692280</ref> <ref>PMID:19369340</ref> <ref>PMID:24622840</ref> <ref>PMID:24410069</ref> Plays a role in host membrane rearrangement that leads to creation of cytoplasmic double-membrane vesicles (DMV) necessary for viral replication. Alone appears incapable to induce membrane curvature, but together with nsp3 is able to induce paired membranes. Nsp3, nsp4 and nsp6 together are sufficient to form DMV.<ref>PMID:23943763</ref> <ref>PMID:24410069</ref> Cleaves the C-terminus of replicase polyprotein at 11 sites. Recognizes substrates containing the core sequence [ILMVF]-Q-\|-[SGACN]. Also able to bind an ADP-ribose-1''-phosphate (ADRP). May cleave host ATP6V1G1 thereby modifying host vacuoles intracellular pH.[PROSITE-ProRule:PRU00772]<ref>PMID:16226257</ref> Plays a role in host membrane rearrangement that leads to creation of cytoplasmic double-membrane vesicles (DMV) necessary for viral replication. Nsp3, nsp4 and nsp6 together are sufficient to form DMV (PubMed:24410069). 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 (PubMed:24991833).<ref>PMID:24991833</ref> <ref>PMID:24410069</ref> 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.<ref>PMID:22039154</ref> 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.<ref>PMID:22039154</ref> May participate in viral replication by acting as a ssRNA-binding protein.<ref>PMID:19153232</ref> 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.<ref>PMID:22635272</ref>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 20:		Line 19:
	</div>		</div>
	<div class="pdbe-citations 6xho" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 6xho" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Virus protease 3D structures\|Virus protease 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: Hcov-sars]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: ~~SARS~~ coronavirus ~~main proteinase~~]]	+	[[Category: Severe acute respiratory syndrome-related coronavirus]]
-	[[Category: Ferre~~, R A~~]]	+	[[Category: Ferre RA]]
-	[[Category: Gajiwala~~, K S~~]]	+	[[Category: Gajiwala KS]]
-	[[Category: Ryan, K]]	+	[[Category: Ryan K]]
-	[[Category: Stewart~~, A E]]~~	+	[[Category: Stewart AE]]
-	~~[[Category: Coronavirus protease inhibitor complex]]~~	+
-	~~[[Category: Viral protein~~]]	+

OCA at 07:37, 4 November 2020

OCA — Wed, 04 Nov 2020 07:37:48 GMT

←Older revision		Revision as of 07:37, 4 November 2020
Line 1:		Line 1:

	==Covalent complex of SARS-CoV main protease with ethyl (4R)-4-({N-[(4-methoxy-1H-indol-2-yl)carbonyl]-L-leucyl}amino)-5-[(3S)-2-oxopyrrolidin-3-yl]pentanoate==		==Covalent complex of SARS-CoV main protease with ethyl (4R)-4-({N-[(4-methoxy-1H-indol-2-yl)carbonyl]-L-leucyl}amino)-5-[(3S)-2-oxopyrrolidin-3-yl]pentanoate==
-	<StructureSection load='6xho' size='340' side='right'caption='[[6xho]]' scene=''>	+	<StructureSection load='6xho' size='340' side='right'caption='[[6xho]], [[Resolution\|resolution]] 1.45Å' 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=6XHO OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6XHO FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6xho]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Hcov-sars Hcov-sars]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6XHO OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6XHO 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=6xho FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6xho OCA], [http://pdbe.org/6xho PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6xho RCSB], [http://www.ebi.ac.uk/pdbsum/6xho PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6xho 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=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=V34:ethyl+(2E,4S)-4-{[N-(4-methoxy-1H-indole-2-carbonyl)-L-leucyl]amino}-5-[(3S)-2-oxopyrrolidin-3-yl]pent-2-enoate'>V34</scene></td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">1a ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=694009 HCoV-SARS])</td></tr>
		+	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/SARS_coronavirus_main_proteinase SARS coronavirus main proteinase], with EC number [http://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'>[http://proteopedia.org/fgij/fg.htm?mol=6xho FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6xho OCA], [http://pdbe.org/6xho PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6xho RCSB], [http://www.ebi.ac.uk/pdbsum/6xho PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6xho ProSAT]</span></td></tr>
	</table>		</table>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/R1A_CVHSA R1A_CVHSA]] The papain-like proteinase (PL-PRO) is responsible for the cleavages located at the N-terminus of 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. Antagonizes innate immune induction of type I interferon by blocking the phosphorylation, dimerization and subsequent nuclear translocation of host IRF-3.<ref>PMID:17024178</ref> <ref>PMID:17692280</ref> <ref>PMID:19369340</ref> The main proteinase 3CL-PRO is responsible for the majority of cleavages as it cleaves the C-terminus of replicase polyprotein at 11 sites. Recognizes substrates containing the core sequence [ILMVF]-Q-\|-[SGACN]. Inhibited by the substrate-analog Cbz-Val-Asn-Ser-Thr-Leu-Gln-CMK (By similarity). Also contains an ADP-ribose-1''-phosphate (ADRP)-binding function.<ref>PMID:17024178</ref> <ref>PMID:17692280</ref> <ref>PMID:19369340</ref> Nsp7-nsp8 hexadecamer may possibly confer processivity to the polymerase, maybe by binding to dsRNA or by producing primers utilized by the latter.<ref>PMID:17024178</ref> <ref>PMID:17692280</ref> <ref>PMID:19369340</ref> Nsp9 is a ssRNA-binding protein.<ref>PMID:17024178</ref> <ref>PMID:17692280</ref> <ref>PMID:19369340</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	The novel coronavirus disease COVID-19 that emerged in 2019 is caused by the virus SARS CoV-2 and named for its close genetic similarity to SARS CoV-1 that caused severe acute respiratory syndrome (SARS) in 2002. Both SARS coronavirus genomes encode two overlapping large polyproteins, which are cleaved at specific sites by a 3C-like cysteine protease (3CL(pro)) in a post-translational processing step that is critical for coronavirus replication. The 3CL(pro) sequences for CoV-1 and CoV-2 viruses are 100% identical in the catalytic domain that carries out protein cleavage. A research effort that focused on the discovery of reversible and irreversible ketone-based inhibitors of SARS CoV-1 3CL(pro) employing ligand-protease structures solved by X-ray crystallography led to the identification of 3 and 4. Preclinical experiments reveal 4 (PF-00835231) as a potent inhibitor of CoV-2 3CL(pro) with suitable pharmaceutical properties to warrant further development as an intravenous treatment for COVID-19.
		+
		+	Discovery of Ketone-Based Covalent Inhibitors of Coronavirus 3CL Proteases for the Potential Therapeutic Treatment of COVID-19.,Hoffman RL, Kania RS, Brothers MA, Davies JF, Ferre RA, Gajiwala KS, He M, Hogan RJ, Kozminski K, Li LY, Lockner JW, Lou J, Marra MT, Mitchell LJ Jr, Murray BW, Nieman JA, Noell S, Planken SP, Rowe T, Ryan K, Smith GJ 3rd, Solowiej JE, Steppan CM, Taggart B J Med Chem. 2020 Oct 15. doi: 10.1021/acs.jmedchem.0c01063. PMID:33054210<ref>PMID:33054210</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 6xho" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Hcov-sars]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Ferre RA]]	+	[[Category: SARS coronavirus main proteinase]]
-	[[Category: Gajiwala KS]]	+	[[Category: Ferre, R A]]
-	[[Category: Ryan K]]	+	[[Category: Gajiwala, K S]]
-	[[Category: Stewart AE]]	+	[[Category: Ryan, K]]
		+	[[Category: Stewart, A E]]
		+	[[Category: Coronavirus protease inhibitor complex]]
		+	[[Category: Viral protein]]

OCA at 14:10, 8 July 2020

OCA — Wed, 08 Jul 2020 14:10:44 GMT

←Older revision		Revision as of 14:10, 8 July 2020
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry 6xho is ON HOLD~~	+	==Covalent complex of SARS-CoV main protease with ethyl (4R)-4-({N-[(4-methoxy-1H-indol-2-yl)carbonyl]-L-leucyl}amino)-5-[(3S)-2-oxopyrrolidin-3-yl]pentanoate==
-		+	<StructureSection load='6xho' size='340' side='right'caption='[[6xho]]' scene=''>
-	~~Authors: Gajiwala, K.S., Ferre, R.A., Ryan, K., Stewart, A.E.~~	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6XHO OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6XHO FirstGlance]. <br>
-	~~Description:~~ Covalent complex of SARS-CoV main protease with ethyl (4R)-4-({N-[(4-methoxy-1H-indol-2-yl)carbonyl]-L-leucyl}amino)-5-[(3S)-2-oxopyrrolidin-3-yl]pentanoate	+	</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=6xho FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6xho OCA], [http://pdbe.org/6xho PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6xho RCSB], [http://www.ebi.ac.uk/pdbsum/6xho PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6xho ProSAT]</span></td></tr>
-	[[Category: ~~Unreleased~~ Structures]]	+	</table>
-	[[Category: Ferre~~, R.A~~]]	+	__TOC__
-	[[Category: ~~Stewart, A.E~~]]	+	</StructureSection>
-	[[Category: Ryan, K]]	+	[[Category: Large Structures]]
-	[[Category: ~~Gajiwala, K.S~~]]	+	[[Category: Ferre RA]]
		+	[[Category: Gajiwala KS]]
		+	[[Category: Ryan K]]
		+	[[Category: Stewart AE]]

OCA: Protected "6xho" [edit=sysop:move=sysop]

OCA — Wed, 24 Jun 2020 18:33:45 GMT

Protected "6xho" [edit=sysop:move=sysop]

←Older revision

Revision as of 18:33, 24 June 2020

OCA: New page: '''Unreleased structure''' The entry 6xho is ON HOLD Authors: Gajiwala, K.S., Ferre, R.A., Ryan, K., Stewart, A.E. Description: Covalent complex of SARS-CoV main protease with ethyl (4...

OCA — Wed, 24 Jun 2020 18:33:43 GMT

New page: '''Unreleased structure''' The entry 6xho is ON HOLD Authors: Gajiwala, K.S., Ferre, R.A., Ryan, K., Stewart, A.E. Description: Covalent complex of SARS-CoV main protease with ethyl (4...

New page

'''Unreleased structure'''

The entry 6xho is ON HOLD

Authors: Gajiwala, K.S., Ferre, R.A., Ryan, K., Stewart, A.E.

Description: Covalent complex of SARS-CoV main protease with ethyl (4R)-4-({N-[(4-methoxy-1H-indol-2-yl)carbonyl]-L-leucyl}amino)-5-[(3S)-2-oxopyrrolidin-3-yl]pentanoate
[[Category: Unreleased Structures]]
[[Category: Ferre, R.A]]
[[Category: Stewart, A.E]]
[[Category: Ryan, K]]
[[Category: Gajiwala, K.S]]