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Specific DNA structural attributes modulate platinum anticancer drug site selection and cross-link generation
Heavy metal compounds have toxic and medicinal potential through capacity to form strong specific bonds with macromolecules, and the interaction of platinum drugs at the major groove nitrogen atom of guanine bases primarily underlies their therapeutic activity. By crystallographic analysis of transi...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2011
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3185412/ https://www.ncbi.nlm.nih.gov/pubmed/21724603 http://dx.doi.org/10.1093/nar/gkr491 |
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author | Wu, Bin Davey, Gabriela E. Nazarov, Alexey A. Dyson, Paul J. Davey, Curt A. |
author_facet | Wu, Bin Davey, Gabriela E. Nazarov, Alexey A. Dyson, Paul J. Davey, Curt A. |
author_sort | Wu, Bin |
collection | PubMed |
description | Heavy metal compounds have toxic and medicinal potential through capacity to form strong specific bonds with macromolecules, and the interaction of platinum drugs at the major groove nitrogen atom of guanine bases primarily underlies their therapeutic activity. By crystallographic analysis of transition metal–and in particular platinum compound–DNA site selectivity in the nucleosome core, we establish that steric accessibility, which is controlled by specific structural parameters of the double helix, modulates initial guanine–metal bond formation. Moreover, DNA conformational features can be linked to both similarities and distinctions in platinum drug adduct formation between the naked and nucleosomal DNA states. Notably, structures that facilitate initial platinum–guanine bond formation can oppose cross-link generation, rationalizing the occurrence of long-lived therapeutically ineffective monofunctional adducts. These findings illuminate DNA structure-dependent reactivity and provide a novel framework for understanding metal–double helix interactions, which should facilitate the development of improved chromatin-targeting medicinal agents. |
format | Online Article Text |
id | pubmed-3185412 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-31854122011-10-04 Specific DNA structural attributes modulate platinum anticancer drug site selection and cross-link generation Wu, Bin Davey, Gabriela E. Nazarov, Alexey A. Dyson, Paul J. Davey, Curt A. Nucleic Acids Res Structural Biology Heavy metal compounds have toxic and medicinal potential through capacity to form strong specific bonds with macromolecules, and the interaction of platinum drugs at the major groove nitrogen atom of guanine bases primarily underlies their therapeutic activity. By crystallographic analysis of transition metal–and in particular platinum compound–DNA site selectivity in the nucleosome core, we establish that steric accessibility, which is controlled by specific structural parameters of the double helix, modulates initial guanine–metal bond formation. Moreover, DNA conformational features can be linked to both similarities and distinctions in platinum drug adduct formation between the naked and nucleosomal DNA states. Notably, structures that facilitate initial platinum–guanine bond formation can oppose cross-link generation, rationalizing the occurrence of long-lived therapeutically ineffective monofunctional adducts. These findings illuminate DNA structure-dependent reactivity and provide a novel framework for understanding metal–double helix interactions, which should facilitate the development of improved chromatin-targeting medicinal agents. Oxford University Press 2011-10 2011-06-30 /pmc/articles/PMC3185412/ /pubmed/21724603 http://dx.doi.org/10.1093/nar/gkr491 Text en © The Author(s) 2011. Published by Oxford University Press. http://creativecommons.org/licenses/by-nc/3.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Structural Biology Wu, Bin Davey, Gabriela E. Nazarov, Alexey A. Dyson, Paul J. Davey, Curt A. Specific DNA structural attributes modulate platinum anticancer drug site selection and cross-link generation |
title | Specific DNA structural attributes modulate platinum anticancer drug site selection and cross-link generation |
title_full | Specific DNA structural attributes modulate platinum anticancer drug site selection and cross-link generation |
title_fullStr | Specific DNA structural attributes modulate platinum anticancer drug site selection and cross-link generation |
title_full_unstemmed | Specific DNA structural attributes modulate platinum anticancer drug site selection and cross-link generation |
title_short | Specific DNA structural attributes modulate platinum anticancer drug site selection and cross-link generation |
title_sort | specific dna structural attributes modulate platinum anticancer drug site selection and cross-link generation |
topic | Structural Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3185412/ https://www.ncbi.nlm.nih.gov/pubmed/21724603 http://dx.doi.org/10.1093/nar/gkr491 |
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