Structure and Stability of Human Telomeric G-Quadruplex with Preclinical 9-Amino Acridines

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...

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Main Authors:	Ferreira, Ruben, Artali, Roberto, Benoit, Adam, Gargallo, Raimundo, Eritja, Ramon, Ferguson, David M., Sham, Yuk Y., Mazzini, Stefania
Format:	Online
Language:	English
Published:	Public Library of Science 2013
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3598906/

id	pubmed-3598906
recordtype	oai_dc
spelling	pubmed-35989062013-04-02 Structure and Stability of Human Telomeric G-Quadruplex with Preclinical 9-Amino Acridines Ferreira, Ruben Artali, Roberto Benoit, Adam Gargallo, Raimundo Eritja, Ramon Ferguson, David M. Sham, Yuk Y. Mazzini, Stefania Research Article 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. Public Library of Science 2013-03-15 /pmc/articles/PMC3598906/ /pubmed/23554865 http://dx.doi.org/10.1371/journal.pone.0057701 Text en © 2013 Ferreira et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Ferreira, Ruben Artali, Roberto Benoit, Adam Gargallo, Raimundo Eritja, Ramon Ferguson, David M. Sham, Yuk Y. Mazzini, Stefania
spellingShingle	Ferreira, Ruben Artali, Roberto Benoit, Adam Gargallo, Raimundo Eritja, Ramon Ferguson, David M. Sham, Yuk Y. Mazzini, Stefania Structure and Stability of Human Telomeric G-Quadruplex with Preclinical 9-Amino Acridines
author_facet	Ferreira, Ruben Artali, Roberto Benoit, Adam Gargallo, Raimundo Eritja, Ramon Ferguson, David M. Sham, Yuk Y. Mazzini, Stefania
author_sort	Ferreira, Ruben
title	Structure and Stability of Human Telomeric G-Quadruplex with Preclinical 9-Amino Acridines
title_short	Structure and Stability of Human Telomeric G-Quadruplex with Preclinical 9-Amino Acridines
title_full	Structure and Stability of Human Telomeric G-Quadruplex with Preclinical 9-Amino Acridines
title_fullStr	Structure and Stability of Human Telomeric G-Quadruplex with Preclinical 9-Amino Acridines
title_full_unstemmed	Structure and Stability of Human Telomeric G-Quadruplex with Preclinical 9-Amino Acridines
title_sort	structure and stability of human telomeric g-quadruplex with preclinical 9-amino acridines
description	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.
publisher	Public Library of Science
publishDate	2013
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3598906/
_version_	1611962582617292800

Structure and Stability of Human Telomeric G-Quadruplex with Preclinical 9-Amino Acridines

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