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4gz0

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Mus Musculus Tdp2-DNA Substrate Analog (5'-6-aminohexanol) Complex

Structural highlights

4gz0 is a 12 chain structure with sequence from Lk3 transgenic mice. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
Related:	4gyz, 4gz1, 4gz2
Gene:	Tdp2, Ttrap (LK3 transgenic mice)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[TYDP2_MOUSE] 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 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.^[1]

Publication Abstract from PubMed

The topoisomerase II (topo II) DNA incision-and-ligation cycle can be poisoned (for example following treatment with cancer chemotherapeutics) to generate cytotoxic DNA double-strand breaks (DSBs) with topo II covalently conjugated to DNA. Tyrosyl-DNA phosphodiesterase 2 (Tdp2) protects genomic integrity by reversing 5'-phosphotyrosyl-linked topo II-DNA adducts. Here, X-ray structures of mouse Tdp2-DNA complexes reveal that Tdp2 beta-2-helix-beta DNA damage-binding 'grasp', helical 'cap' and DNA lesion-binding elements fuse to form an elongated protein-DNA conjugate substrate-interaction groove. The Tdp2 DNA-binding surface is highly tailored for engagement of 5'-adducted single-stranded DNA ends and restricts nonspecific endonucleolytic or exonucleolytic processing. Structural, mutational and functional analyses support a single-metal ion catalytic mechanism for the exonuclease-endonuclease-phosphatase (EEP) nuclease superfamily and establish a molecular framework for targeted small-molecule blockade of Tdp2-mediated resistance to anticancer topoisomerase drugs.

Mechanism of repair of 5'-topoisomerase II-DNA adducts by mammalian tyrosyl-DNA phosphodiesterase 2.,Schellenberg MJ, Appel CD, Adhikari S, Robertson PD, Ramsden DA, Williams RS Nat Struct Mol Biol. 2012 Oct 28. doi: 10.1038/nsmb.2418. PMID:23104055^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Zeng Z, Sharma A, Ju L, Murai J, Umans L, Vermeire L, Pommier Y, Takeda S, Huylebroeck D, Caldecott KW, El-Khamisy SF. TDP2 promotes repair of topoisomerase I-mediated DNA damage in the absence of TDP1. Nucleic Acids Res. 2012 Sep 1;40(17):8371-80. Epub 2012 Jun 26. PMID:22740648 doi:http://dx.doi.org/10.1093/nar/gks622
↑ Schellenberg MJ, Appel CD, Adhikari S, Robertson PD, Ramsden DA, Williams RS. Mechanism of repair of 5'-topoisomerase II-DNA adducts by mammalian tyrosyl-DNA phosphodiesterase 2. Nat Struct Mol Biol. 2012 Oct 28. doi: 10.1038/nsmb.2418. PMID:23104055 doi:http://dx.doi.org/10.1038/nsmb.2418

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4gz0"

@@ Line 1: / Line 1: @@
 ==Mus Musculus Tdp2-DNA Substrate Analog (5'-6-aminohexanol) Complex==
 <StructureSection load='4gz0' size='340' side='right' caption='[[4gz0]], [[Resolution|resolution]] 2.11&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4gz0]] is a 12 chain structure with sequence from [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4GZ0 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4GZ0 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4gz0]] is a 12 chain structure with sequence from [http://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4GZ0 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4GZ0 FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6AH:6-AMINOHEXAN-1-OL'>6AH</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4gyz|4gyz]], [[4gz1|4gz1]], [[4gz2|4gz2]]</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Tdp2, Ttrap ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 Mus musculus])</td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Tdp2, Ttrap ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 LK3 transgenic mice])</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=4gz0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4gz0 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4gz0 RCSB], [http://www.ebi.ac.uk/pdbsum/4gz0 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=4gz0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4gz0 OCA], [http://pdbe.org/4gz0 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4gz0 RCSB], [http://www.ebi.ac.uk/pdbsum/4gz0 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4gz0 ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 18: / Line 19: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 4gz0" style="background-color:#fffaf0;"></div>
 ==See Also==
@@ Line 25: / Line 27: @@
 __TOC__
 </StructureSection>
-[[Category: Mus musculus]]
+[[Category: Lk3 transgenic mice]]
 [[Category: Schellenberg, M J]]
 [[Category: Williams, R S]]

4gz0

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Current revision

Mus Musculus Tdp2-DNA Substrate Analog (5'-6-aminohexanol) Complex

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

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