5GWK

Human topoisomerase IIalpha in complex with DNA and etoposide

Summary for 5GWK

• Entry DOI: 10.2210/pdb5gwk/pdb
• Related: 3QX3 5GWI 5GWJ
• Descriptor: 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)
• Functional Keywords: type ii topoisomerase, anti-cancer drug, topoii cleavage complex, isomerase-dna-isomerase inhibitor complex, isomerase/dna/isomerase inhibitor
• Biological source: Homo sapiens (Human); More
• Cellular location: Cytoplasm : P11388
• Total number of polymer chains: 6
• Total formula weight: 199340.44

Authors

Wang, Y.R.,Wu, C.C.,Chan, N.L. (deposition date: 2016-09-12, release date: 2017-08-23, Last modification date: 2023-11-08)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (3.152 Å)