6n19 - Revision history

OCA at 06:43, 11 October 2023

2023-10-11T06:43:07Z

←Older revision		Revision as of 06:43, 11 October 2023
Line 3:		Line 3:
	<StructureSection load='6n19' size='340' side='right'caption='[[6n19]], [[Resolution\|resolution]] 1.50Å' scene=''>		<StructureSection load='6n19' size='340' side='right'caption='[[6n19]], [[Resolution\|resolution]] 1.50Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6n19]] is a 2 chain structure with sequence from [~~http~~://en.wikipedia.org/wiki/~~Human Human~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6N19 OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=6N19 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6n19]] is a 2 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=6N19 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6N19 FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=K8V:4-[(4-carboxybutanoyl)amino]benzene-1,2-dicarboxylic+acid'>K8V</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]] 1.501Å</td></tr>
-	~~<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">TDP1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])~~</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=K8V:4-[(4-carboxybutanoyl)amino]benzene-1,2-dicarboxylic+acid'>K8V</scene></td></tr>
-	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=6n19 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6n19 OCA], [~~http~~://pdbe.org/6n19 PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=6n19 RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/6n19 PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=6n19 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=6n19 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6n19 OCA], [https://pdbe.org/6n19 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6n19 RCSB], [https://www.ebi.ac.uk/pdbsum/6n19 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6n19 ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
-	[~~[http~~://www.uniprot.org/uniprot/TYDP1_HUMAN TYDP1_HUMAN]] Defects in TDP1 are the cause of spinocerebellar ataxia autosomal recessive with axonal neuropathy (SCAN1) [MIM:[~~http~~://omim.org/entry/607250 607250]]. SCAN1 is an autosomal recessive cerebellar ataxia (ARCA) associated with peripheral axonal motor and sensory neuropathy, distal muscular atrophy, pes cavus and steppage gait as seen in Charcot-Marie-Tooth neuropathy. All affected individuals have normal intelligence.<ref>PMID:16141202</ref> <ref>PMID:15647511</ref> <ref>PMID:12244316</ref> <ref>PMID:17948061</ref> <ref>PMID:15920477</ref>	+	[https://www.uniprot.org/uniprot/TYDP1_HUMAN TYDP1_HUMAN] Defects in TDP1 are the cause of spinocerebellar ataxia autosomal recessive with axonal neuropathy (SCAN1) [MIM:[https://omim.org/entry/607250 607250]. SCAN1 is an autosomal recessive cerebellar ataxia (ARCA) associated with peripheral axonal motor and sensory neuropathy, distal muscular atrophy, pes cavus and steppage gait as seen in Charcot-Marie-Tooth neuropathy. All affected individuals have normal intelligence.<ref>PMID:16141202</ref> <ref>PMID:15647511</ref> <ref>PMID:12244316</ref> <ref>PMID:17948061</ref> <ref>PMID:15920477</ref>
	== Function ==		== Function ==
-	[~~[http~~://www.uniprot.org/uniprot/TYDP1_HUMAN TYDP1_HUMAN]] DNA repair enzyme that can remove a variety of covalent adducts from DNA through hydrolysis of a 3'-phosphodiester bond, giving rise to DNA with a free 3' phosphate. Catalyzes the hydrolysis of dead-end complexes between DNA and the topoisomerase I active site tyrosine residue. Hydrolyzes 3'-phosphoglycolates on protruding 3' ends on DNA double-strand breaks due to DNA damage by radiation and free radicals. Acts on blunt-ended double-strand DNA breaks and on single-stranded DNA. Has low 3'exonuclease activity and can remove a single nucleoside from the 3'end of DNA and RNA molecules with 3'hydroxyl groups. Has no exonuclease activity towards DNA or RNA with a 3'phosphate.<ref>PMID:12023295</ref> <ref>PMID:15111055</ref> <ref>PMID:15811850</ref> <ref>PMID:16141202</ref> <ref>PMID:22822062</ref>	+	[https://www.uniprot.org/uniprot/TYDP1_HUMAN TYDP1_HUMAN] DNA repair enzyme that can remove a variety of covalent adducts from DNA through hydrolysis of a 3'-phosphodiester bond, giving rise to DNA with a free 3' phosphate. Catalyzes the hydrolysis of dead-end complexes between DNA and the topoisomerase I active site tyrosine residue. Hydrolyzes 3'-phosphoglycolates on protruding 3' ends on DNA double-strand breaks due to DNA damage by radiation and free radicals. Acts on blunt-ended double-strand DNA breaks and on single-stranded DNA. Has low 3'exonuclease activity and can remove a single nucleoside from the 3'end of DNA and RNA molecules with 3'hydroxyl groups. Has no exonuclease activity towards DNA or RNA with a 3'phosphate.<ref>PMID:12023295</ref> <ref>PMID:15111055</ref> <ref>PMID:15811850</ref> <ref>PMID:16141202</ref> <ref>PMID:22822062</ref>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 21:		Line 21:
	</div>		</div>
	<div class="pdbe-citations 6n19" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 6n19" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Phosphodiesterase 3D structures\|Phosphodiesterase 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Burke~~, T R~~]]	+	[[Category: Burke Jr TR]]
-	[[Category: Kiselev, E]]	+	[[Category: Kiselev E]]
-	[[Category: Lountos~~, G T~~]]	+	[[Category: Lountos GT]]
-	[[Category: Needle, D]]	+	[[Category: Needle D]]
-	[[Category: Pommier, Y]]	+	[[Category: Pommier Y]]
-	[[Category: Tropea~~, J E~~]]	+	[[Category: Tropea JE]]
-	[[Category: Waugh~~, D S~~]]	+	[[Category: Waugh DS]]
-	[[Category: Zhao~~, X Z]]~~	+	[[Category: Zhao XZ]]
-	~~[[Category: Anti-cancer drug design]]~~	+
-	~~[[Category: Dna binding protein]]~~	+
-	~~[[Category: Fragment based drug design]]~~	+
-	~~[[Category: Hydrolase~~]]	+

OCA at 11:40, 13 November 2019

2019-11-13T11:40:19Z

←Older revision		Revision as of 11:40, 13 November 2019
Line 3:		Line 3:
	<StructureSection load='6n19' size='340' side='right'caption='[[6n19]], [[Resolution\|resolution]] 1.50Å' scene=''>		<StructureSection load='6n19' size='340' side='right'caption='[[6n19]], [[Resolution\|resolution]] 1.50Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6n19]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6N19 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6N19 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6n19]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6N19 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6N19 FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=K8V:4-[(4-carboxybutanoyl)amino]benzene-1,2-dicarboxylic+acid'>K8V</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=K8V:4-[(4-carboxybutanoyl)amino]benzene-1,2-dicarboxylic+acid'>K8V</scene></td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">TDP1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6n19 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6n19 OCA], [http://pdbe.org/6n19 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6n19 RCSB], [http://www.ebi.ac.uk/pdbsum/6n19 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6n19 ProSAT]</span></td></tr>		<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6n19 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6n19 OCA], [http://pdbe.org/6n19 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6n19 RCSB], [http://www.ebi.ac.uk/pdbsum/6n19 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6n19 ProSAT]</span></td></tr>
	</table>		</table>
Line 24:		Line 25:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
	[[Category: Burke, T R]]		[[Category: Burke, T R]]

OCA at 05:54, 3 July 2019

2019-07-03T05:54:18Z

←Older revision		Revision as of 05:54, 3 July 2019
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 6n19 is ~~ON HOLD~~ ~~until Paper~~ Publication	+	==Crystal structure of Tdp1 catalytic domain in complex with compound XZ578==
		+	<StructureSection load='6n19' size='340' side='right'caption='[[6n19]], [[Resolution\|resolution]] 1.50Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[6n19]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6N19 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6N19 FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=K8V:4-[(4-carboxybutanoyl)amino]benzene-1,2-dicarboxylic+acid'>K8V</scene></td></tr>
		+	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6n19 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6n19 OCA], [http://pdbe.org/6n19 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6n19 RCSB], [http://www.ebi.ac.uk/pdbsum/6n19 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6n19 ProSAT]</span></td></tr>
		+	</table>
		+	== Disease ==
		+	[[http://www.uniprot.org/uniprot/TYDP1_HUMAN TYDP1_HUMAN]] Defects in TDP1 are the cause of spinocerebellar ataxia autosomal recessive with axonal neuropathy (SCAN1) [MIM:[http://omim.org/entry/607250 607250]]. SCAN1 is an autosomal recessive cerebellar ataxia (ARCA) associated with peripheral axonal motor and sensory neuropathy, distal muscular atrophy, pes cavus and steppage gait as seen in Charcot-Marie-Tooth neuropathy. All affected individuals have normal intelligence.<ref>PMID:16141202</ref> <ref>PMID:15647511</ref> <ref>PMID:12244316</ref> <ref>PMID:17948061</ref> <ref>PMID:15920477</ref>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/TYDP1_HUMAN TYDP1_HUMAN]] DNA repair enzyme that can remove a variety of covalent adducts from DNA through hydrolysis of a 3'-phosphodiester bond, giving rise to DNA with a free 3' phosphate. Catalyzes the hydrolysis of dead-end complexes between DNA and the topoisomerase I active site tyrosine residue. Hydrolyzes 3'-phosphoglycolates on protruding 3' ends on DNA double-strand breaks due to DNA damage by radiation and free radicals. Acts on blunt-ended double-strand DNA breaks and on single-stranded DNA. Has low 3'exonuclease activity and can remove a single nucleoside from the 3'end of DNA and RNA molecules with 3'hydroxyl groups. Has no exonuclease activity towards DNA or RNA with a 3'phosphate.<ref>PMID:12023295</ref> <ref>PMID:15111055</ref> <ref>PMID:15811850</ref> <ref>PMID:16141202</ref> <ref>PMID:22822062</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Tyrosyl DNA-phosphodiesterase I (TDP1) repairs type IB topoisomerase (TOP1) cleavage complexes generated by TOP1 inhibitors commonly used as anticancer agents. TDP1 also removes DNA 3' end blocking lesions generated by chain-terminating nucleosides and alkylating agents, and base oxidation both in the nuclear and mitochondrial genomes. Combination therapy with TDP1 inhibitors is proposed to synergize with topoisomerase targeting drugs to enhance selectivity against cancer cells exhibiting deficiencies in parallel DNA repair pathways. A crystallographic fragment screening campaign against the catalytic domain of TDP1 was conducted to identify new lead compounds. Crystal structures revealed two fragments that bind to the TDP1 active site and exhibit inhibitory activity against TDP1. These fragments occupy a similar position in the TDP1 active site as seen in prior crystal structures of TDP1 with bound vanadate, a transition state mimic. Using structural insights into fragment binding, several fragment derivatives have been prepared and evaluated in biochemical assays. These results demonstrate that fragment-based methods can be a highly feasible approach toward the discovery of small-molecule chemical scaffolds to target TDP1, and for the first time, we provide co-crystal structures of small molecule inhibitors bound to TDP1, which could serve for the rational development of medicinal TDP1 inhibitors.

-	~~Authors:~~ Lountos~~, G.T.~~, Zhao~~, X.Z.~~, Kiselev, E., Tropea~~, J.E.~~, Needle, D., Burke ~~Jr.~~, T.R.~~, Pommier, Y~~.~~, Waugh, D~~.S.	+	Identification of a ligand binding hot spot and structural motifs replicating aspects of tyrosyl-DNA phosphodiesterase I (TDP1) phosphoryl recognition by crystallographic fragment cocktail screening.,Lountos GT, Zhao XZ, Kiselev E, Tropea JE, Needle D, Pommier Y, Burke TR, Waugh DS Nucleic Acids Res. 2019 Jun 14. pii: 5519170. doi: 10.1093/nar/gkz515. PMID:31199869<ref>PMID:31199869</ref>

-	~~Description: Crystal structure~~ of ~~Tdp1 catalytic domain in complex with compound XZ578~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	~~[[Category~~: ~~Unreleased Structures]]~~	+	</div>
-	~~[[Category: T.R]]~~	+	<div class="pdbe-citations 6n19" style="background-color:#fffaf0;"></div>
-	[[Category: ~~Pommier, Y~~]]	+	== References ==
-	[[Category: ~~Waugh~~, ~~D.S~~]]	+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Large Structures]]
		+	[[Category: Burke, T R]]
	[[Category: Kiselev, E]]		[[Category: Kiselev, E]]
-	[[Category: ~~Zhao~~, ~~X.Z]]~~	+	[[Category: Lountos, G T]]
-	~~[[Category: Tropea, J.E]]~~	+
-	~~[[Category: Burke Jr~~]]	+
	[[Category: Needle, D]]		[[Category: Needle, D]]
-	[[Category: ~~Lountos~~, ~~G.T~~]]	+	[[Category: Pommier, Y]]
		+	[[Category: Tropea, J E]]
		+	[[Category: Waugh, D S]]
		+	[[Category: Zhao, X Z]]
		+	[[Category: Anti-cancer drug design]]
		+	[[Category: Dna binding protein]]
		+	[[Category: Fragment based drug design]]
		+	[[Category: Hydrolase]]

OCA at 10:32, 16 January 2019

2019-01-16T10:32:21Z

←Older revision		Revision as of 10:32, 16 January 2019
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 6n19 is ON HOLD	+	The entry 6n19 is ON HOLD until Paper Publication

	Authors: Lountos, G.T., Zhao, X.Z., Kiselev, E., Tropea, J.E., Needle, D., Burke Jr., T.R., Pommier, Y., Waugh, D.S.		Authors: Lountos, G.T., Zhao, X.Z., Kiselev, E., Tropea, J.E., Needle, D., Burke Jr., T.R., Pommier, Y., Waugh, D.S.
Line 7:		Line 7:
	Description: Crystal structure of Tdp1 catalytic domain in complex with compound XZ578		Description: Crystal structure of Tdp1 catalytic domain in complex with compound XZ578
	[[Category: Unreleased Structures]]		[[Category: Unreleased Structures]]
-	[[Category: Waugh, D.S]]
-	[[Category: Lountos, G.T]]
	[[Category: T.R]]		[[Category: T.R]]
	[[Category: Pommier, Y]]		[[Category: Pommier, Y]]
		+	[[Category: Waugh, D.S]]
	[[Category: Kiselev, E]]		[[Category: Kiselev, E]]
	[[Category: Zhao, X.Z]]		[[Category: Zhao, X.Z]]
Line 16:		Line 15:
	[[Category: Burke Jr]]		[[Category: Burke Jr]]
	[[Category: Needle, D]]		[[Category: Needle, D]]
		+	[[Category: Lountos, G.T]]

OCA: Protected "6n19" [edit=sysop:move=sysop]

2018-11-14T06:48:41Z

Protected "6n19" [edit=sysop:move=sysop]

←Older revision

Revision as of 06:48, 14 November 2018

OCA: New page: '''Unreleased structure''' The entry 6n19 is ON HOLD Authors: Lountos, G.T., Zhao, X.Z., Kiselev, E., Tropea, J.E., Needle, D., Burke Jr., T.R., Pommier, Y., Waugh, D.S. Description: C...

2018-11-14T06:48:40Z

New page: '''Unreleased structure''' The entry 6n19 is ON HOLD Authors: Lountos, G.T., Zhao, X.Z., Kiselev, E., Tropea, J.E., Needle, D., Burke Jr., T.R., Pommier, Y., Waugh, D.S. Description: C...

New page

'''Unreleased structure'''

The entry 6n19 is ON HOLD

Authors: Lountos, G.T., Zhao, X.Z., Kiselev, E., Tropea, J.E., Needle, D., Burke Jr., T.R., Pommier, Y., Waugh, D.S.

Description: Crystal structure of Tdp1 catalytic domain in complex with compound XZ578
[[Category: Unreleased Structures]]
[[Category: Waugh, D.S]]
[[Category: Lountos, G.T]]
[[Category: T.R]]
[[Category: Pommier, Y]]
[[Category: Kiselev, E]]
[[Category: Zhao, X.Z]]
[[Category: Tropea, J.E]]
[[Category: Burke Jr]]
[[Category: Needle, D]]