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Título : Kinetic evidence for interaction of TMPyP4 with two different G-quadruplex conformations of human telomeric DNA
Autor : Pérez Arnáiz, Cristina
Busto Vázquez, Natalia
Santolaya, Javier
Leal Villalba, José María
Barone, Giampaolo .
García Ruiz, Begoña
Publicado en: Biochimica et biophysica acta (BBA) - general subjects. 2018, V. 1862, n. 3, p. 522-531
Editorial : Elsevier
Fecha de publicación : mar-2018
Fecha de disponibilidad: mar-2019
ISSN : 0304-4165
DOI: 10.1016/j.bbagen.2017.10.020
Resumen : Background: Stabilization of G-quadruplex helices by small ligands has attracted growing attention because they inhibit the activity of the enzyme telomerase, which is overexpressed in> 80% cancer cells. TMPyP4, one of the most studied G-quadruplex ligands, is used as a model to show that the ligands can exhibit different binding features with different conformations of a human telomeric specific sequence. Methods: UV–Vis, FRET melting Assay, Isothermal Titration Calorimetry, Time-resolved Fluorescence lifetime, T-Jump and Molecular Dynamics. Results: TMPyP4 yields two different complexes with two Tel22 telomeric conformations in the presence of Na+ or K+. T-Jump kinetic experiments show that the rates of formation and dissociation of these complexes in the ms time scale differ by one order of magnitude. MD simulations reveal that, in K+ buffer, “hybrid 1” conformation yields kinetic constants on interaction with TMPyP4 one order lower than “hybrid 2”. The binding involves π–π stacking with external loop bases. Conclusions: For the first time we show that for a particular buffer TMPyP4 interacts in a kinetically different way with the two Tel22 conformations even if the complexes formed are thermodynamically indistinguishable. General significance: G-quadruplexes, endowed with technological applications and potential impact on regulation mechanisms, define a new research field. The possibility of building different conformations from same sequence is a complex issue that confers G-quadruplexes very interesting features. The obtaining of reliable kinetic data constitutes an efficient tool to determine reaction mechanisms between conformations and small molecules.
Palabras clave: Tel22 conformations
Fast reactions
Molecular dynamics
Licencia: https://creativecommons.org/licenses/by-nc-nd/4.0/
URI : http://hdl.handle.net/10259/4746
Versión del editor: https://doi.org/10.1016/j.bbagen.2017.10.020
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