View source for 5gwj


==Structure of a Human topoisomerase IIbeta fragment in complex with DNA and E7873S==
<StructureSection load='5gwj' size='340' side='right'caption='[[5gwj]], [[Resolution|resolution]] 2.57&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5gwj]] is a 6 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=5GWJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5GWJ FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.566&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=N2S:chloro{4,5-di(amino-kappaN)-N-[9-(4-hydroxy-3,5-dimethoxyphenyl)-8-oxo-5,5a,6,8,8a,9-hexahydro-2H-furo[3,4 6,7]naphtho[2,3-d][1,3]dioxol-5-yl]pentanamide}platinum'>N2S</scene>, <scene name='pdbligand=N2W:chloro{4,5-di(amino-kappaN)-N-[9-(4-hydroxy-3,5-dimethoxyphenyl)-8-oxo-5,5a,6,8,8a,9-hexahydro-2H-furo[3,4 6,7]naphtho[2,3-d][1,3]dioxol-5-yl]pentanamide}platinum'>N2W</scene></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=5gwj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5gwj OCA], [https://pdbe.org/5gwj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5gwj RCSB], [https://www.ebi.ac.uk/pdbsum/5gwj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5gwj ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/TOP2B_HUMAN TOP2B_HUMAN] Control of topological states of DNA by transient breakage and subsequent rejoining of DNA strands. Topoisomerase II makes double-strand breaks. Indirectly involved in vitamin D-coupled transcription regulation via its association with the WINAC complex, a chromatin-remodeling complex recruited by vitamin D receptor (VDR), which is required for the ligand-bound VDR-mediated transrepression of the CYP27B1 gene.<ref>PMID:10684600</ref> <ref>PMID:12837248</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Human type II topoisomerase (Top2) isoforms, hTop2alpha and hTop2beta, are targeted by some of the most successful anticancer drugs. These drugs induce Top2-mediated DNA cleavage to trigger cell-death pathways. The potency of these drugs correlates positively with their efficacy in stabilizing the enzyme-mediated DNA breaks. Structural analysis of hTop2alpha and hTop2beta revealed the presence of methionine residues in the drug-binding pocket, we therefore tested whether a tighter Top2-drug association may be accomplished by introducing a methionine-reactive Pt2+ into a drug to further stabilize the DNA break. Herein, we synthesized an organoplatinum compound, etoplatin-N2beta, by replacing the methionine-juxtaposing group of the drug etoposide with a cis-dichlorodiammineplatinum(II) moiety. Compared to etoposide, etoplatin-N2beta more potently inhibits both human Top2s. While the DNA breaks arrested by etoposide can be rejoined, those captured by etoplatin-N2beta are practically irreversible. Crystallographic analyses of hTop2beta complexed with DNA and etoplatin-N2beta demonstrate coordinate bond formation between Pt2+ and a flanking methionine. Notably, this stable coordinate tether can be loosened by disrupting the structural integrity of drug-binding pocket, suggesting that Pt2+ coordination chemistry may allow for the development of potent inhibitors with protein conformation-dependent reversibility. This approach may be exploited to achieve isoform-specific targeting of human Top2s.

Producing irreversible topoisomerase II-mediated DNA breaks by site-specific Pt(II)-methionine coordination chemistry.,Wang YR, Chen SF, Wu CC, Liao YW, Lin TS, Liu KT, Chen YS, Li TK, Chien TC, Chan NL Nucleic Acids Res. 2017 Oct 13;45(18):10861-10871. doi: 10.1093/nar/gkx742. PMID:28977631<ref>PMID:28977631</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5gwj" style="background-color:#fffaf0;"></div>

==See Also==
*[[Topoisomerase 3D structures|Topoisomerase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Synthetic construct]]
[[Category: Chan NL]]
[[Category: Chen SF]]
[[Category: Wang YR]]
[[Category: Wu CC]]