7kg7 - Revision history

OCA at 15:24, 18 October 2023

OCA — Wed, 18 Oct 2023 15:24:21 GMT

←Older revision		Revision as of 15:24, 18 October 2023
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	<StructureSection load='7kg7' size='340' side='right'caption='[[7kg7]], [[Resolution\|resolution]] 1.85Å' scene=''>		<StructureSection load='7kg7' size='340' side='right'caption='[[7kg7]], [[Resolution\|resolution]] 1.85Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[7kg7]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/~~Human Human~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7KG7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7KG7 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[7kg7]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7KG7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7KG7 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=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=WDJ:8-{~~[~~2-(1,1-dioxo-1lambda~6~,4-thiazinan-4-yl)ethyl~~]~~sulfanyl}-~~1~~,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione'>WDJ</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]] 1.85Å</td></tr>
-	<tr id='~~NonStdRes~~'><td class="sblockLbl"><b>[[~~Non-Standard_Residue~~\|~~NonStd Res~~:]]</b></td><td class="sblockDat"><scene name='pdbligand=CME:S,S-(2-HYDROXYETHYL)THIOCYSTEINE'>CME</scene><~~/td></tr>~~	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CME:S,S-(2-HYDROXYETHYL)THIOCYSTEINE'>CME</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=WDJ:8-{[2-(1,1-dioxo-1lambda~6~,4-thiazinan-4-yl)ethyl]sulfanyl}-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione'>WDJ</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;'>[[7kg3\|7kg3]]~~, ~~[[7kg1\|7kg1]], [[7kg8\|7kg8]], [[7kfp\|7kfp]], [[7kg0\|7kg0]], [[7kg6\|7kg6]]~~<~~/div></td></tr>~~	+
-	~~<tr id~~='~~gene'><td class~~=~~"sblockLbl"><b>[[Gene\|Gene~~:~~]]</b~~></td><~~td class="sblockDat">PARG ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>~~	+
-	~~<tr id~~='~~activity'><td class~~=~~"sblockLbl"><b>Activity~~:~~</b></td><td class="sblockDat"><span class='plainlinks'>~~[~~https://en.wikipedia.org/wiki/Poly(ADP~~-~~ribose)_glycohydrolase Poly~~(~~ADP~~-~~ribose~~) ~~glycohydrolase~~], ~~with EC number [https://www.brenda~~-~~enzymes.info/php/result_flat.php4?ecno=~~3.2~~.1.143 3.2.1.143]~~ </~~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=7kg7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7kg7 OCA], [https://pdbe.org/7kg7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7kg7 RCSB], [https://www.ebi.ac.uk/pdbsum/7kg7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7kg7 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=7kg7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7kg7 OCA], [https://pdbe.org/7kg7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7kg7 RCSB], [https://www.ebi.ac.uk/pdbsum/7kg7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7kg7 ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
-	[[https://www.uniprot.org/uniprot/PARG_HUMAN PARG_HUMAN]] Poly(ADP-ribose) synthesized after DNA damage is only present transiently and is rapidly degraded by poly(ADP-ribose) glycohydrolase. PARG acts both as an endo- and exoglycosidase, releasing PAR of different length as well as ADP-ribose monomers. Required for retinoid acid-dependent gene transactivation, probably by dePARsylating histone demethylase KDM4D, allowing chromatin derepression at RAR-dependent gene promoters.<ref>PMID:23102699</ref>	+	[https://www.uniprot.org/uniprot/PARG_HUMAN PARG_HUMAN] Poly(ADP-ribose) synthesized after DNA damage is only present transiently and is rapidly degraded by poly(ADP-ribose) glycohydrolase. PARG acts both as an endo- and exoglycosidase, releasing PAR of different length as well as ADP-ribose monomers. Required for retinoid acid-dependent gene transactivation, probably by dePARsylating histone demethylase KDM4D, allowing chromatin derepression at RAR-dependent gene promoters.<ref>PMID:23102699</ref>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
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	</div>		</div>
	<div class="pdbe-citations 7kg7" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 7kg7" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Poly(ADP-ribose) glycohydrolase 3D structures\|Poly(ADP-ribose) glycohydrolase 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Ahmed, Z]]	+	[[Category: Ahmed Z]]
-	[[Category: Balapiti-Modarage~~, L P.F~~]]	+	[[Category: Balapiti-Modarage LPF]]
-	[[Category: Brosey~~, C A~~]]	+	[[Category: Brosey CA]]
-	[[Category: Jones~~, D E~~]]	+	[[Category: Jones DE]]
-	[[Category: Tainer~~, J A~~]]	+	[[Category: Tainer JA]]
-	[[Category: Warden~~, L S]]~~	+	[[Category: Warden LS]]
-	~~[[Category: Hydrolase]]~~	+
-	~~[[Category: Hydrolase inhibitor complex]]~~	+
-	~~[[Category: Hydrolase-hydrolase inhibitor complex]]~~	+
-	~~[[Category: Methyl xanthine~~]]	+

OCA at 14:59, 17 June 2021

OCA — Thu, 17 Jun 2021 14:59:52 GMT

←Older revision		Revision as of 14:59, 17 June 2021
Line 1:		Line 1:

	==Structure of human PARG complexed with PARG-292==		==Structure of human PARG complexed with PARG-292==
-	<StructureSection load='7kg7' size='340' side='right'caption='[[7kg7]]' scene=''>	+	<StructureSection load='7kg7' size='340' side='right'caption='[[7kg7]], [[Resolution\|resolution]] 1.85Å' 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=7KG7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7KG7 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[7kg7]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7KG7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7KG7 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=7kg7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7kg7 OCA], [https://pdbe.org/7kg7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7kg7 RCSB], [https://www.ebi.ac.uk/pdbsum/7kg7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7kg7 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=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=WDJ:8-{[2-(1,1-dioxo-1lambda~6~,4-thiazinan-4-yl)ethyl]sulfanyl}-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione'>WDJ</scene></td></tr>
		+	<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=CME:S,S-(2-HYDROXYETHYL)THIOCYSTEINE'>CME</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;'>[[7kg3\|7kg3]], [[7kg1\|7kg1]], [[7kg8\|7kg8]], [[7kfp\|7kfp]], [[7kg0\|7kg0]], [[7kg6\|7kg6]]</div></td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">PARG ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
		+	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Poly(ADP-ribose)_glycohydrolase Poly(ADP-ribose) glycohydrolase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.2.1.143 3.2.1.143] </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=7kg7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7kg7 OCA], [https://pdbe.org/7kg7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7kg7 RCSB], [https://www.ebi.ac.uk/pdbsum/7kg7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7kg7 ProSAT]</span></td></tr>
	</table>		</table>
		+	== Function ==
		+	[[https://www.uniprot.org/uniprot/PARG_HUMAN PARG_HUMAN]] Poly(ADP-ribose) synthesized after DNA damage is only present transiently and is rapidly degraded by poly(ADP-ribose) glycohydrolase. PARG acts both as an endo- and exoglycosidase, releasing PAR of different length as well as ADP-ribose monomers. Required for retinoid acid-dependent gene transactivation, probably by dePARsylating histone demethylase KDM4D, allowing chromatin derepression at RAR-dependent gene promoters.<ref>PMID:23102699</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Arrival of the novel SARS-CoV-2 has launched a worldwide effort to identify both pre-approved and novel therapeutics targeting the viral proteome, highlighting the urgent need for efficient drug discovery strategies. Even with effective vaccines, infection is possible, and at-risk populations would benefit from effective drug compounds that reduce the lethality and lasting damage of COVID-19 infection. The CoV-2 MacroD-like macrodomain (Mac1) is implicated in viral pathogenicity by disrupting host innate immunity through its mono (ADP-ribosyl) hydrolase activity, making it a prime target for antiviral therapy. We therefore solved the structure of CoV-2 Mac1 from non-structural protein 3 (Nsp3) and applied structural and sequence-based genetic tracing, including newly determined A. pompejana MacroD2 and GDAP2 amino acid sequences, to compare and contrast CoV-2 Mac1 with the functionally related human DNA-damage signaling factor poly (ADP-ribose) glycohydrolase (PARG). Previously, identified targetable features of the PARG active site allowed us to develop a pharmacologically useful PARG inhibitor (PARGi). Here, we developed a focused chemical library and determined 6 novel PARGi X-ray crystal structures for comparative analysis. We applied this knowledge to discovery of CoV-2 Mac1 inhibitors by combining computation and structural analysis to identify PARGi fragments with potential to bind the distal-ribose and adenosyl pockets of the CoV-2 Mac1 active site. Scaffold development of these PARGi fragments has yielded two novel compounds, PARG-345 and PARG-329, that crystallize within the Mac1 active site, providing critical structure-activity data and a pathway for inhibitor optimization. The reported structural findings demonstrate ways to harness our PARGi synthesis and characterization pipeline to develop CoV-2 Mac1 inhibitors targeting the ADP-ribose active site. Together, these structural and computational analyses reveal a path for accelerating development of antiviral therapeutics from pre-existing drug optimization pipelines.
		+
		+	Targeting SARS-CoV-2 Nsp3 macrodomain structure with insights from human poly(ADP-ribose) glycohydrolase (PARG) structures with inhibitors.,Brosey CA, Houl JH, Katsonis P, Balapiti-Modarage LPF, Bommagani S, Arvai A, Moiani D, Bacolla A, Link T, Warden LS, Lichtarge O, Jones DE, Ahmed Z, Tainer JA Prog Biophys Mol Biol. 2021 Feb 23. pii: S0079-6107(21)00007-9. doi:, 10.1016/j.pbiomolbio.2021.02.002. PMID:33636189<ref>PMID:33636189</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 7kg7" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Ahmed Z]]	+	[[Category: Ahmed, Z]]
-	[[Category: Balapiti-Modarage ~~LPF~~]]	+	[[Category: Balapiti-Modarage, L P.F]]
-	[[Category: Brosey CA]]	+	[[Category: Brosey, C A]]
-	[[Category: Jones DE]]	+	[[Category: Jones, D E]]
-	[[Category: Tainer JA]]	+	[[Category: Tainer, J A]]
-	[[Category: Warden LS]]	+	[[Category: Warden, L S]]
		+	[[Category: Hydrolase]]
		+	[[Category: Hydrolase inhibitor complex]]
		+	[[Category: Hydrolase-hydrolase inhibitor complex]]
		+	[[Category: Methyl xanthine]]

OCA at 17:22, 10 March 2021

OCA — Wed, 10 Mar 2021 17:22:00 GMT

←Older revision		Revision as of 17:22, 10 March 2021
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 7kg7 is ~~ON HOLD until Apr 16 2022~~	+	==Structure of human PARG complexed with PARG-292==
-		+	<StructureSection load='7kg7' size='340' side='right'caption='[[7kg7]]' scene=''>
-	~~Authors~~:	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7KG7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7KG7 FirstGlance]. <br>
-	~~Description~~:	+	</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=7kg7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7kg7 OCA], [https://pdbe.org/7kg7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7kg7 RCSB], [https://www.ebi.ac.uk/pdbsum/7kg7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7kg7 ProSAT]</span></td></tr>
-	[[Category: ~~Unreleased Structures~~]]	+	</table>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Large Structures]]
		+	[[Category: Ahmed Z]]
		+	[[Category: Balapiti-Modarage LPF]]
		+	[[Category: Brosey CA]]
		+	[[Category: Jones DE]]
		+	[[Category: Tainer JA]]
		+	[[Category: Warden LS]]

OCA at 19:09, 28 October 2020

OCA — Wed, 28 Oct 2020 19:09:43 GMT

←Older revision		Revision as of 19:09, 28 October 2020
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 7kg7 is ON HOLD	+	The entry 7kg7 is ON HOLD until Apr 16 2022

	Authors:		Authors:

OCA: Protected "7kg7" [edit=sysop:move=sysop]

OCA — Wed, 21 Oct 2020 06:56:27 GMT

Protected "7kg7" [edit=sysop:move=sysop]

←Older revision

Revision as of 06:56, 21 October 2020

OCA: New page: '''Unreleased structure''' The entry 7kg7 is ON HOLD Authors: Description: Category: Unreleased Structures

OCA — Wed, 21 Oct 2020 06:56:25 GMT

New page: '''Unreleased structure''' The entry 7kg7 is ON HOLD Authors: Description: Category: Unreleased Structures

New page

'''Unreleased structure'''

The entry 7kg7 is ON HOLD

Authors:

Description:
[[Category: Unreleased Structures]]