RT info:eu-repo/semantics/article
T1 Kinetic evidence for interaction of TMPyP4 with two different G-quadruplex conformations of human telomeric DNA
A1 Pérez Arnáiz, Cristina
A1 Busto Vázquez, Natalia
A1 Santolaya, Javier
A1 Leal Villalba, José María
A1 Barone, Giampaolo
A1 García Ruiz, Begoña
K1 Tel22 conformations
K1 TMPyP4
K1 Fast reactions
K1 Molecular dynamics
K1 Chemistry, Physical and theoretical
K1 Química física
AB Background: Stabilization of G-quadruplex helices by small ligands has attracted growing attention because theyinhibit the activity of the enzyme telomerase, which is overexpressed in> 80% cancer cells. TMPyP4, one of themost studied G-quadruplex ligands, is used as a model to show that the ligands can exhibit different bindingfeatures 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 thems time scale differ by one order of magnitude. MD simulations reveal that, in K+ buffer, “hybrid 1” conformationyields kinetic constants on interaction with TMPyP4 one order lower than “hybrid 2”. The bindinginvolves π–π stacking with external loop bases.Conclusions: For the first time we show that for a particular buffer TMPyP4 interacts in a kinetically differentway 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 regulationmechanisms, define a new research field. The possibility of building different conformations from samesequence is a complex issue that confers G-quadruplexes very interesting features. The obtaining of reliablekinetic data constitutes an efficient tool to determine reaction mechanisms between conformations and smallmolecules.
PB Elsevier
SN 0304-4165
YR 2018
FD 2018-03
LK http://hdl.handle.net/10259/4746
UL http://hdl.handle.net/10259/4746
LA eng
NO “laCaixa” Foundation (project OSLC-2012-007), MINECO, (CTQ2014-58812-C2-2-R) and Junta de Castilla y León, (BU042U16), FEDERFunds Spain
DS Repositorio Institucional de la Universidad de Burgos
RD 04-dic-2024