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Title: | Structure and stability of human telomeric G-quadruplex with preclinical 9-amino acridines |
Author: | Ferreira Aguilera, Rubén Artali, Roberto Benoit, Adam Gargallo Gómez, Raimundo Eritja i Casadellà, Ramon Ferguson, David M. Sham, Yuk Y. Mazzini, Stefania |
Keywords: | ADN Sistemes d'administració de medicaments Telòmer Protons Oligonucleòtids DNA Drug delivery devices Telomere Protons Oligonucleotides |
Issue Date: | 15-Mar-2013 |
Publisher: | Public Library of Science (PLoS) |
Abstract: | G-quadruplexes are higher-order DNA structures formed from guanine-rich sequences, and have been identified as attractive anticancer drug targets. Elucidating the three-dimensional structure of G-quadruplex with 9-amino acridines and the specific interactions involved in binding selectivity are the key to understanding their mechanism of action. Fluorescence titration assays, competitive dialysis and NMR studies have been used to study the binding specificity of 9-amino acridines to DNA. Structural models of the complexes with the telomeric DNA G-quadruplex based on NMR measurements were developed and further examined by molecular dynamics simulations and free energy calculations. Selective binding of 9-amino acridines for G-quadruplex sequences were observed. These compounds bind between A and G-tetrads, involving significant π-π interactions and several strong hydrogen bonds. The specific interactions between different moieties of the 9-amino acridines to the DNA were examined and shown to play a significant role in governing the overall stabilities of DNA G-quadruplex complexes. Both 9-amino acridines, with similar binding affinities to the G-quadruplex, were shown to induce different level of structural stabilization through intercalation. This unique property of altering structural stability is likely a contributing factor for affecting telomerase function and, subsequently, the observed differences in the anticancer activities between the two 9-amino acridines. |
Note: | Reproducció del document publicat a: https://doi.org/10.1371/journal.pone.0057701 |
It is part of: | PLoS One, 2013, vol. 8, num. 3, p. e57701 |
URI: | http://hdl.handle.net/2445/124528 |
Related resource: | https://doi.org/10.1371/journal.pone.0057701 |
ISSN: | 1932-6203 |
Appears in Collections: | Articles publicats en revistes (Enginyeria Química i Química Analítica) |
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