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==Crystal structure of the complex of Tdp1 with duplex DNA==
==Crystal structure of the complex of Tdp1 with duplex DNA==
<StructureSection load='5nw9' size='340' side='right' caption='[[5nw9]], [[Resolution|resolution]] 2.04&Aring;' scene=''>
<StructureSection load='5nw9' size='340' side='right'caption='[[5nw9]], [[Resolution|resolution]] 2.04&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[5nw9]] is a 3 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5NW9 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5NW9 FirstGlance]. <br>
<table><tr><td colspan='2'>[[5nw9]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5NW9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5NW9 FirstGlance]. <br>
</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=5nw9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5nw9 OCA], [http://pdbe.org/5nw9 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5nw9 RCSB], [http://www.ebi.ac.uk/pdbsum/5nw9 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5nw9 ProSAT]</span></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]] 2.04&#8491;</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=5nw9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5nw9 OCA], [https://pdbe.org/5nw9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5nw9 RCSB], [https://www.ebi.ac.uk/pdbsum/5nw9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5nw9 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;">
== Publication Abstract from PubMed ==
Tyrosyl-DNA phosphodiesterase (Tdp1) is a DNA 3'-end processing enzyme that repairs topoisomerase 1B-induced DNA damage. We use a new tool combining site-specific DNA-protein cross-linking with mass spectrometry to identify Tdp1 interactions with DNA. A conserved phenylalanine (F259) of Tdp1, required for efficient DNA processing in biochemical assays, cross-links to defined positions in DNA substrates. Crystal structures of Tdp1-DNA complexes capture the DNA repair machinery after 3'-end cleavage; these reveal how Tdp1 coordinates the 3'-phosphorylated product of nucleosidase activity and accommodates duplex DNA. A hydrophobic wedge splits the DNA ends, directing the scissile strand through a channel towards the active site. The F259 side-chain stacks against the -3 base pair, delimiting the junction of duplexed and melted DNA, and fixes the scissile strand in the channel. Our results explain why Tdp1 cleavage is non-processive and provide a molecular basis for DNA 3'-end processing by Tdp1.
 
Structural basis for DNA 3'-end processing by human tyrosyl-DNA phosphodiesterase 1.,Flett FJ, Ruksenaite E, Armstrong LA, Bharati S, Carloni R, Morris ER, Mackay CL, Interthal H, Richardson JM Nat Commun. 2018 Jan 2;9(1):24. doi: 10.1038/s41467-017-02530-z. PMID:29295983<ref>PMID:29295983</ref>
 
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5nw9" style="background-color:#fffaf0;"></div>
 
==See Also==
*[[Phosphodiesterase 3D structures|Phosphodiesterase 3D structures]]
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Morris, E R]]
[[Category: Homo sapiens]]
[[Category: Richardson, J M]]
[[Category: Large Structures]]
[[Category: Ruksenaite, E]]
[[Category: Synthetic construct]]
[[Category: Dna repair]]
[[Category: Morris ER]]
[[Category: Hydrolase]]
[[Category: Richardson JM]]
[[Category: Nucleosidase]]
[[Category: Ruksenaite E]]
[[Category: Phosphotyrosine diesterase]]
[[Category: Protein-dna complex]]
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