5GWK

Human topoisomerase IIalpha in complex with DNA and etoposide

5GWK の概要

• エントリーDOI: 10.2210/pdb5gwk/pdb
• 関連するPDBエントリー: 3QX3 5GWI 5GWJ
• 分子名称: DNA topoisomerase 2-alpha, DNA (5'-D(P*AP*GP*CP*CP*GP*AP*GP*C)-3'), DNA (5'-D(P*TP*GP*CP*AP*GP*CP*TP*CP*GP*GP*CP*T)-3'), ... (5 entities in total)
• 機能のキーワード: type ii topoisomerase, anti-cancer drug, topoii cleavage complex, isomerase-dna-isomerase inhibitor complex, isomerase/dna/isomerase inhibitor
• 由来する生物種: Homo sapiens (Human); 詳細
• 細胞内の位置: Cytoplasm : P11388
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 199340.44

構造登録者

Wang, Y.R.,Wu, C.C.,Chan, N.L. (登録日: 2016-09-12, 公開日: 2017-08-23, 最終更新日: 2024-11-20)

主引用文献

Wang, Y.R.,Chen, S.F.,Wu, C.C.,Liao, Y.W.,Lin, T.S.,Liu, K.T.,Chen, Y.S.,Li, T.K.,Chien, T.C.,Chan, N.L.
Producing irreversible topoisomerase II-mediated DNA breaks by site-specific Pt(II)-methionine coordination chemistry
Nucleic Acids Res., 45:10861-10871, 2017

PubMed Abstract: Human type II topoisomerase (Top2) isoforms, hTop2α and hTop2β, 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 hTop2α and hTop2β 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-N2β, by replacing the methionine-juxtaposing group of the drug etoposide with a cis-dichlorodiammineplatinum(II) moiety. Compared to etoposide, etoplatin-N2β more potently inhibits both human Top2s. While the DNA breaks arrested by etoposide can be rejoined, those captured by etoplatin-N2β are practically irreversible. Crystallographic analyses of hTop2β complexed with DNA and etoplatin-N2β 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.

PubMed: 28977631
DOI: 10.1093/nar/gkx742

実験手法

X-RAY DIFFRACTION (3.152 Å)