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| | ==Human topoisomerase IIalpha in complex with DNA and etoposide== | | ==Human topoisomerase IIalpha in complex with DNA and etoposide== |
| - | <StructureSection load='5gwk' size='340' side='right' caption='[[5gwk]], [[Resolution|resolution]] 3.15Å' scene=''> | + | <StructureSection load='5gwk' size='340' side='right'caption='[[5gwk]], [[Resolution|resolution]] 3.15Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5gwk]] is a 6 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=5GWK OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5GWK FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5gwk]] 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=5GWK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5GWK FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EVP:(5S,5AR,8AR,9R)-9-(4-HYDROXY-3,5-DIMETHOXYPHENYL)-8-OXO-5,5A,6,8,8A,9-HEXAHYDROFURO[3,4 6,7]NAPHTHO[2,3-D][1,3]DIOXOL-5-YL+4,6-O-[(1R)-ETHYLIDENE]-BETA-D-GLUCOPYRANOSIDE'>EVP</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]] 3.152Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3qx3|3qx3]], [[5gwi|5gwi]], [[5gwj|5gwj]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EVP:(5S,5AR,8AR,9R)-9-(4-HYDROXY-3,5-DIMETHOXYPHENYL)-8-OXO-5,5A,6,8,8A,9-HEXAHYDROFURO[3,4 6,7]NAPHTHO[2,3-D][1,3]DIOXOL-5-YL+4,6-O-[(1R)-ETHYLIDENE]-BETA-D-GLUCOPYRANOSIDE'>EVP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">TOP2A, TOP2 ([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'>[https://proteopedia.org/fgij/fg.htm?mol=5gwk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5gwk OCA], [https://pdbe.org/5gwk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5gwk RCSB], [https://www.ebi.ac.uk/pdbsum/5gwk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5gwk ProSAT]</span></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/DNA_topoisomerase_(ATP-hydrolyzing) DNA topoisomerase (ATP-hydrolyzing)], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=5.99.1.3 5.99.1.3] </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=5gwk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5gwk OCA], [http://pdbe.org/5gwk PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5gwk RCSB], [http://www.ebi.ac.uk/pdbsum/5gwk PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5gwk ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/TOP2A_HUMAN TOP2A_HUMAN]] Control of topological states of DNA by transient breakage and subsequent rejoining of DNA strands. Topoisomerase II makes double-strand breaks. Essential during mitosis and meiosis for proper segregation of daughter chromosomes.<ref>PMID:22323612</ref> | + | [https://www.uniprot.org/uniprot/TOP2A_HUMAN TOP2A_HUMAN] Control of topological states of DNA by transient breakage and subsequent rejoining of DNA strands. Topoisomerase II makes double-strand breaks. Essential during mitosis and meiosis for proper segregation of daughter chromosomes.<ref>PMID:22323612</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 5gwk" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 5gwk" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Topoisomerase 3D structures|Topoisomerase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Chan, N L]] | + | [[Category: Large Structures]] |
| - | [[Category: Wang, Y R]] | + | [[Category: Synthetic construct]] |
| - | [[Category: Wu, C C]] | + | [[Category: Chan NL]] |
| - | [[Category: Anti-cancer drug]] | + | [[Category: Wang YR]] |
| - | [[Category: Isomerase-dna-isomerase inhibitor complex]] | + | [[Category: Wu CC]] |
| - | [[Category: Topoii cleavage complex]]
| + | |
| - | [[Category: Type ii topoisomerase]]
| + | |
| Structural highlights
Function
TOP2A_HUMAN Control of topological states of DNA by transient breakage and subsequent rejoining of DNA strands. Topoisomerase II makes double-strand breaks. Essential during mitosis and meiosis for proper segregation of daughter chromosomes.[1]
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[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Lee S, Jung SR, Heo K, Byl JA, Deweese JE, Osheroff N, Hohng S. DNA cleavage and opening reactions of human topoisomerase IIalpha are regulated via Mg2+-mediated dynamic bending of gate-DNA. Proc Natl Acad Sci U S A. 2012 Feb 21;109(8):2925-30. doi:, 10.1073/pnas.1115704109. Epub 2012 Feb 9. PMID:22323612 doi:http://dx.doi.org/10.1073/pnas.1115704109
- ↑ Wang YR, Chen SF, Wu CC, Liao YW, Lin TS, Liu KT, Chen YS, Li TK, Chien TC, Chan NL. Producing irreversible topoisomerase II-mediated DNA breaks by site-specific Pt(II)-methionine coordination chemistry. Nucleic Acids Res. 2017 Oct 13;45(18):10861-10871. doi: 10.1093/nar/gkx742. PMID:28977631 doi:http://dx.doi.org/10.1093/nar/gkx742
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