5j3p - Revision history

OCA at 10:44, 6 September 2023

2023-09-06T10:44:16Z

←Older revision		Revision as of 10:44, 6 September 2023
Line 3:		Line 3:
	<StructureSection load='5j3p' size='340' side='right'caption='[[5j3p]], [[Resolution\|resolution]] 3.10Å' scene=''>		<StructureSection load='5j3p' size='340' side='right'caption='[[5j3p]], [[Resolution\|resolution]] 3.10Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5j3p]] 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=5J3P OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://proteopedia.org/fgij/fg.htm?mol=5J3P FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5j3p]] 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=5J3P OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5J3P FirstGlance]. <br>
-	</td></tr><tr id='~~ligand~~'><td class="sblockLbl"><b>[[~~Ligand~~\|~~Ligands~~:]]</b></td><td class="sblockDat" id="~~ligandDat~~">~~<scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>~~, ~~<scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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]] 3.1Å</td></tr>
-	<tr id='~~gene~~'><td class="sblockLbl"><b>[[~~Gene~~\|~~Gene~~:]]</b></td><td class="sblockDat">~~TDP2, EAP2, TTRAP, AD-022 ([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=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></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=5j3p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5j3p OCA], [~~http~~://pdbe.org/5j3p PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=5j3p RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/5j3p PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=5j3p 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=5j3p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5j3p OCA], [https://pdbe.org/5j3p PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5j3p RCSB], [https://www.ebi.ac.uk/pdbsum/5j3p PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5j3p ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
-	[~~[http~~://www.uniprot.org/uniprot/TYDP2_HUMAN TYDP2_HUMAN]] Autosomal recessive cerebellar ataxia-epilepsy-intellectual disability syndrome due to TUD deficiency.	+	[https://www.uniprot.org/uniprot/TYDP2_HUMAN TYDP2_HUMAN] Autosomal recessive cerebellar ataxia-epilepsy-intellectual disability syndrome due to TUD deficiency.
	== Function ==		== Function ==
-	[~~[http~~://www.uniprot.org/uniprot/TYDP2_HUMAN TYDP2_HUMAN]] DNA repair enzyme that can remove a variety of covalent adducts from DNA through hydrolysis of a 5'-phosphodiester bond, giving rise to DNA with a free 5' phosphate. Catalyzes the hydrolysis of dead-end complexes between DNA and the topoisomerase 2 (TOP2) active site tyrosine residue. Hydrolyzes 5'-phosphoglycolates on protruding 5' ends on DNA double-strand breaks (DSBs) due to DNA damage by radiation and free radicals. The 5'-tyrosyl DNA phosphodiesterase activity can enable the repair of TOP2-induced DSBs without the need for nuclease activity, creating a 'clean' DSB with 5'-phosphate termini that are ready for ligation. Has preference for single-stranded DNA or duplex DNA with a 4 base pair overhang as substrate. Has also 3'-tyrosyl DNA phosphodiesterase activity, but less efficiently and much slower than TDP1. Constitutes the major if not only 5'-tyrosyl-DNA phosphodiesterase in cells. Also acts as a 5'-tyrosyl-RNA phosphodiesterase following picornavirus infection: its activity is hijacked by picornavirus and acts by specifically cleaving the protein-RNA covalent linkage generated during the viral genomic RNA replication steps of a picornavirus infection, without impairing the integrity of viral RNA. Also acts as an adapter by participating in the specific activation of MAP3K7/TAK1 in response to TGF-beta: associates with components of the TGF-beta receptor-TRAF6-TAK1 signaling module and promotes their ubiquitination dependent complex formation. Involved in non-canonical TGF-beta induced signaling routes. May also act as a negative regulator of ETS1 and may inhibit NF-kappa-B activation. Acts as a regulator of ribosome biogenesis following stress.<ref>PMID:19794497</ref> <ref>PMID:21030584</ref> <ref>PMID:21921940</ref> <ref>PMID:21980489</ref> <ref>PMID:22405347</ref> <ref>PMID:22822062</ref> <ref>PMID:22908287</ref>	+	[https://www.uniprot.org/uniprot/TYDP2_HUMAN TYDP2_HUMAN] DNA repair enzyme that can remove a variety of covalent adducts from DNA through hydrolysis of a 5'-phosphodiester bond, giving rise to DNA with a free 5' phosphate. Catalyzes the hydrolysis of dead-end complexes between DNA and the topoisomerase 2 (TOP2) active site tyrosine residue. Hydrolyzes 5'-phosphoglycolates on protruding 5' ends on DNA double-strand breaks (DSBs) due to DNA damage by radiation and free radicals. The 5'-tyrosyl DNA phosphodiesterase activity can enable the repair of TOP2-induced DSBs without the need for nuclease activity, creating a 'clean' DSB with 5'-phosphate termini that are ready for ligation. Has preference for single-stranded DNA or duplex DNA with a 4 base pair overhang as substrate. Has also 3'-tyrosyl DNA phosphodiesterase activity, but less efficiently and much slower than TDP1. Constitutes the major if not only 5'-tyrosyl-DNA phosphodiesterase in cells. Also acts as a 5'-tyrosyl-RNA phosphodiesterase following picornavirus infection: its activity is hijacked by picornavirus and acts by specifically cleaving the protein-RNA covalent linkage generated during the viral genomic RNA replication steps of a picornavirus infection, without impairing the integrity of viral RNA. Also acts as an adapter by participating in the specific activation of MAP3K7/TAK1 in response to TGF-beta: associates with components of the TGF-beta receptor-TRAF6-TAK1 signaling module and promotes their ubiquitination dependent complex formation. Involved in non-canonical TGF-beta induced signaling routes. May also act as a negative regulator of ETS1 and may inhibit NF-kappa-B activation. Acts as a regulator of ribosome biogenesis following stress.<ref>PMID:19794497</ref> <ref>PMID:21030584</ref> <ref>PMID:21921940</ref> <ref>PMID:21980489</ref> <ref>PMID:22405347</ref> <ref>PMID:22822062</ref> <ref>PMID:22908287</ref>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
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	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Caldecott~~, K W~~]]	+	[[Category: Caldecott KW]]
-	[[Category: Hornyak, P]]	+	[[Category: Hornyak P]]
-	[[Category: Oliver~~, A W~~]]	+	[[Category: Oliver AW]]
-	[[Category: Pearl~~, L H]]~~	+	[[Category: Pearl LH]]
-	~~[[Category: Catalytic domain]]~~	+
-	~~[[Category: Dna phosphodiesterase 2]]~~	+
-	~~[[Category: Hydrolase]]~~	+
-	~~[[Category: Tyrosyl~~]]	+

OCA at 07:27, 10 June 2020

2020-06-10T07:27:52Z

←Older revision		Revision as of 07:27, 10 June 2020
Line 1:		Line 1:

	==Crystal structure of the catalytic domain of human tyrosyl DNA phosphodiesterase 2==		==Crystal structure of the catalytic domain of human tyrosyl DNA phosphodiesterase 2==
-	<StructureSection load='5j3p' size='340' side='right' caption='[[5j3p]], [[Resolution\|resolution]] 3.10Å' scene=''>	+	<StructureSection load='5j3p' size='340' side='right'caption='[[5j3p]], [[Resolution\|resolution]] 3.10Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5j3p]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5J3P OCA]. For a <b>guided tour on the structure components</b> use [http://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=5J3P FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5j3p]] 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=5J3P OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5J3P FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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=5j3p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5j3p OCA], [http://pdbe.org/5j3p PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5j3p RCSB], [http://www.ebi.ac.uk/pdbsum/5j3p PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5j3p ProSAT]</span></td></tr>	+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">TDP2, EAP2, TTRAP, AD-022 ([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://proteopedia.org/fgij/fg.htm?mol=5j3p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5j3p OCA], [http://pdbe.org/5j3p PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5j3p RCSB], [http://www.ebi.ac.uk/pdbsum/5j3p PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5j3p ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
Line 20:		Line 21:
	</div>		</div>
	<div class="pdbe-citations 5j3p" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 5j3p" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Phosphodiesterase 3D structures\|Phosphodiesterase 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human]]
		+	[[Category: Large Structures]]
	[[Category: Caldecott, K W]]		[[Category: Caldecott, K W]]
	[[Category: Hornyak, P]]		[[Category: Hornyak, P]]

OCA at 17:54, 12 July 2016

2016-07-12T17:54:13Z

←Older revision		Revision as of 17:54, 12 July 2016
Line 5:		Line 5:
	<table><tr><td colspan='2'>[[5j3p]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5J3P OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5J3P FirstGlance]. <br>		<table><tr><td colspan='2'>[[5j3p]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5J3P OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5J3P FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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=5j3p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5j3p OCA], [http://pdbe.org/5j3p PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5j3p RCSB], [http://www.ebi.ac.uk/pdbsum/5j3p PDBsum]</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=5j3p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5j3p OCA], [http://pdbe.org/5j3p PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5j3p RCSB], [http://www.ebi.ac.uk/pdbsum/5j3p PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5j3p ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==

OCA: Protected "5j3p" [edit=sysop:move=sysop]

2016-05-11T03:31:17Z

Protected "5j3p" [edit=sysop:move=sysop]

←Older revision

Revision as of 03:31, 11 May 2016

OCA: New page: ==Crystal structure of the catalytic domain of human tyrosyl DNA phosphodiesterase 2== == Structural highlights ==
<table><tr><td colspan='2'>[[5j3p]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5J3P OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5J3P FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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=5j3p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5j3p OCA], [http://pdbe.org/5j3p PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5j3p RCSB], [http://www.ebi.ac.uk/pdbsum/5j3p PDBsum]</span></td></tr>
</table>
== Disease ==
[[http://www.uniprot.org/uniprot/TYDP2_HUMAN TYDP2_HUMAN]] Autosomal recessive cerebellar ataxia-epilepsy-intellectual disability syndrome due to TUD deficiency.
== Function ==
[[http://www.uniprot.org/uniprot/TYDP2_HUMAN TYDP2_HUMAN]] DNA repair enzyme that can remove a variety of covalent adducts from DNA through hydrolysis of a 5'-phosphodiester bond, giving rise to DNA with a free 5' phosphate. Catalyzes the hydrolysis of dead-end complexes between DNA and the topoisomerase 2 (TOP2) active site tyrosine residue. Hydrolyzes 5'-phosphoglycolates on protruding 5' ends on DNA double-strand breaks (DSBs) due to DNA damage by radiation and free radicals. The 5'-tyrosyl DNA phosphodiesterase activity can enable the repair of TOP2-induced DSBs without the need for nuclease activity, creating a 'clean' DSB with 5'-phosphate termini that are ready for ligation. Has preference for single-stranded DNA or duplex DNA with a 4 base pair overhang as substrate. Has also 3'-tyrosyl DNA phosphodiesterase activity, but less efficiently and much slower than TDP1. Constitutes the major if not only 5'-tyrosyl-DNA phosphodiesterase in cells. Also acts as a 5'-tyrosyl-RNA phosphodiesterase following picornavirus infection: its activity is hijacked by picornavirus and acts by specifically cleaving the protein-RNA covalent linkage generated during the viral genomic RNA replication steps of a picornavirus infection, without impairing the integrity of viral RNA. Also acts as an adapter by participating in the specific activation of MAP3K7/TAK1 in response to TGF-beta: associates with components of the TGF-beta receptor-TRAF6-TAK1 signaling module and promotes their ubiquitination dependent complex formation. Involved in non-canonical TGF-beta induced signaling routes. May also act as a negative regulator of ETS1 and may inhibit NF-kappa-B activation. Acts as a regulator of ribosome biogenesis following stress.<ref>PMID:19794497</ref> <ref>PMID:21030584</ref> <ref>PMID:21921940</ref> <ref>PMID:21980489</ref> <ref>PMID:22405347</ref> <ref>PMID:22822062</ref> <ref>PMID:22908287</ref>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
TDP2 is a 5'-tyrosyl DNA phosphodiesterase important for the repair of DNA adducts generated by non-productive (abortive) activity of topoisomerase II. TDP2 facilitates therapeutic resistance to topoisomerase poisons, which are widely used in the treatment of a range of cancer types. Consequently, TDP2 is an interesting target for the development of small molecule inhibitors that could restore sensitivity to topoisomerase-directed therapies. Previous studies identified a class of deazaflavin-based molecules that showed inhibitory activity against TDP2 at therapeutically useful concentrations, but their mode of action was uncertain. We have confirmed that the deazaflavin series inhibits TDP2 enzyme activity in a fluorescence-based assay, suitable for HTS-screening. We have gone on to determine crystal structures of these compounds bound to a 'humanised' form of murine TDP2. The structures reveal their novel mode of action as competitive ligands for the binding site of an incoming DNA substrate, and point the way to generating novel and potent inhibitors of TDP2.

Mode of action of DNA-competitive small molecule inhibitors of tyrosyl DNA phosphodiesterase 2.,Hornyak P, Askwith T, Walker S, Komulainen E, Paradowski M, Pennicott LE, Bartlett EJ, Brissett NC, Raoof A, Watson M, Jordan AM, Ogilvie DJ, Ward SE, Atack JR, Pearl LH, Caldecott KW, Oliver AW Biochem J. 2016 Apr 20. pii: BCJ20160180. PMID:27099339<ref>PMID:27099339</ref>

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5j3p" style="background-color:#fffaf0;"></div>
== References ==
<references/>
TOC
</StructureSection>
[[Category: Caldecott, K W]]
[[Category: Hornyak, P]]
[[Category: Oliver, A W]]
[[Category: Pearl, L H]]
[[Category: Catalytic domain]]
[[Category: Dna phosphodiesterase 2]]
[[Category: Hydrolase]]
[[Category: Tyrosyl]]