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| | ==Structure of a Human topoisomerase IIbeta fragment in complex with DNA and E7873R== | | ==Structure of a Human topoisomerase IIbeta fragment in complex with DNA and E7873R== |
| - | <StructureSection load='5gwi' size='340' side='right' caption='[[5gwi]], [[Resolution|resolution]] 2.74Å' scene=''> | + | <StructureSection load='5gwi' size='340' side='right'caption='[[5gwi]], [[Resolution|resolution]] 2.74Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5gwi]] 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=5GWI OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5GWI FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5gwi]] 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=5GWI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5GWI FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=N2N:dichloro{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'>N2N</scene>, <scene name='pdbligand=N2R:dichloro{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'>N2R</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]] 2.737Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5gwj|5gwj]], [[5gwk|5gwk]]</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=N2N:N-[(5R,5aS,8aR,9R)-9-(3,5-dimethoxy-4-oxidanyl-phenyl)-8-oxidanylidene-5a,6,8a,9-tetrahydro-5H-[2]benzofuro[5,6-f][1,3]benzodioxol-5-yl]-3-[(4R)-2,2-bis(chloranyl)-1$l^{4},3$l^{4}-diaza-2$l^{4}-platinacyclopent-4-yl]propanamide'>N2N</scene>, <scene name='pdbligand=N2R:dichloro{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'>N2R</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">TOP2B ([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=5gwi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5gwi OCA], [https://pdbe.org/5gwi PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5gwi RCSB], [https://www.ebi.ac.uk/pdbsum/5gwi PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5gwi 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=5gwi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5gwi OCA], [http://pdbe.org/5gwi PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5gwi RCSB], [http://www.ebi.ac.uk/pdbsum/5gwi PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5gwi ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://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> | + | [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;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 5gwi" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 5gwi" 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: Chen, S F]] | + | [[Category: Synthetic construct]] |
| - | [[Category: Wang, Y R]] | + | [[Category: Chan NL]] |
| - | [[Category: Wu, C C]] | + | [[Category: Chen SF]] |
| - | [[Category: Anti-cancer drug]] | + | [[Category: Wang YR]] |
| - | [[Category: Isomerase-dna complex]] | + | [[Category: Wu CC]] |
| - | [[Category: Isomerase-dna-isomerase inhibitor complex]]
| + | |
| - | [[Category: Topoii cleavage complex]]
| + | |
| - | [[Category: Type ii topoisomerase]]
| + | |
| Structural highlights
Function
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.[1] [2]
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[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ West KL, Meczes EL, Thorn R, Turnbull RM, Marshall R, Austin CA. Mutagenesis of E477 or K505 in the B' domain of human topoisomerase II beta increases the requirement for magnesium ions during strand passage. Biochemistry. 2000 Feb 15;39(6):1223-33. PMID:10684600
- ↑ Kitagawa H, Fujiki R, Yoshimura K, Mezaki Y, Uematsu Y, Matsui D, Ogawa S, Unno K, Okubo M, Tokita A, Nakagawa T, Ito T, Ishimi Y, Nagasawa H, Matsumoto T, Yanagisawa J, Kato S. The chromatin-remodeling complex WINAC targets a nuclear receptor to promoters and is impaired in Williams syndrome. Cell. 2003 Jun 27;113(7):905-17. PMID:12837248
- ↑ 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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