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Producing irreversible topoisomerase II-mediated DNA breaks by site-specific Pt(II)-methionine coordination chemistry

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-m...

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Autores principales: Wang, Ying-Ren, Chen, Shin-Fu, Wu, Chyuan-Chuan, Liao, Yi-Wen, Lin, Te-Sheng, Liu, Ko-Ting, Chen, Yi-Song, Li, Tsai-Kun, Chien, Tun-Cheng, Chan, Nei-Li
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5737487/
https://www.ncbi.nlm.nih.gov/pubmed/28977631
http://dx.doi.org/10.1093/nar/gkx742
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author Wang, Ying-Ren
Chen, Shin-Fu
Wu, Chyuan-Chuan
Liao, Yi-Wen
Lin, Te-Sheng
Liu, Ko-Ting
Chen, Yi-Song
Li, Tsai-Kun
Chien, Tun-Cheng
Chan, Nei-Li
author_facet Wang, Ying-Ren
Chen, Shin-Fu
Wu, Chyuan-Chuan
Liao, Yi-Wen
Lin, Te-Sheng
Liu, Ko-Ting
Chen, Yi-Song
Li, Tsai-Kun
Chien, Tun-Cheng
Chan, Nei-Li
author_sort Wang, Ying-Ren
collection PubMed
description 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 Pt(2+) 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 Pt(2+) and a flanking methionine. Notably, this stable coordinate tether can be loosened by disrupting the structural integrity of drug-binding pocket, suggesting that Pt(2+) 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.
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spelling pubmed-57374872018-01-09 Producing irreversible topoisomerase II-mediated DNA breaks by site-specific Pt(II)-methionine coordination chemistry Wang, Ying-Ren Chen, Shin-Fu Wu, Chyuan-Chuan Liao, Yi-Wen Lin, Te-Sheng Liu, Ko-Ting Chen, Yi-Song Li, Tsai-Kun Chien, Tun-Cheng Chan, Nei-Li Nucleic Acids Res Structural Biology 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 Pt(2+) 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 Pt(2+) and a flanking methionine. Notably, this stable coordinate tether can be loosened by disrupting the structural integrity of drug-binding pocket, suggesting that Pt(2+) 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. Oxford University Press 2017-10-13 2017-08-24 /pmc/articles/PMC5737487/ /pubmed/28977631 http://dx.doi.org/10.1093/nar/gkx742 Text en © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Structural Biology
Wang, Ying-Ren
Chen, Shin-Fu
Wu, Chyuan-Chuan
Liao, Yi-Wen
Lin, Te-Sheng
Liu, Ko-Ting
Chen, Yi-Song
Li, Tsai-Kun
Chien, Tun-Cheng
Chan, Nei-Li
Producing irreversible topoisomerase II-mediated DNA breaks by site-specific Pt(II)-methionine coordination chemistry
title Producing irreversible topoisomerase II-mediated DNA breaks by site-specific Pt(II)-methionine coordination chemistry
title_full Producing irreversible topoisomerase II-mediated DNA breaks by site-specific Pt(II)-methionine coordination chemistry
title_fullStr Producing irreversible topoisomerase II-mediated DNA breaks by site-specific Pt(II)-methionine coordination chemistry
title_full_unstemmed Producing irreversible topoisomerase II-mediated DNA breaks by site-specific Pt(II)-methionine coordination chemistry
title_short Producing irreversible topoisomerase II-mediated DNA breaks by site-specific Pt(II)-methionine coordination chemistry
title_sort producing irreversible topoisomerase ii-mediated dna breaks by site-specific pt(ii)-methionine coordination chemistry
topic Structural Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5737487/
https://www.ncbi.nlm.nih.gov/pubmed/28977631
http://dx.doi.org/10.1093/nar/gkx742
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