Ligand-Induced Conformational Changes with Cation Ejection upon Binding to Human Telomeric DNA G-Quadruplexes

Abstract

The rational design of ligands targeting human telomeric DNA G-quadruplexes is a complex problem due to the structural polymorphism that these sequences can adopt in physiological conditions. Moreover, the ability of ligands to switch conformational equilibria between different G-quadruplex structures is often overlooked in docking approaches. Here, we demonstrate that three of the most potent G-quadruplex ligands (360A, Phen-DC3, and pyridostatin) induce conformational changes of telomeric DNA G-quadruplexes to an antiparallel structure (as determined by circular dichroism) containing only one specifically coordinated K(+) (as determined by electrospray mass spectrometry) and, hence, presumably only two consecutive G-quartets. Control ligands TrisQ, known to bind preferentially to hybrid than to antiparallel structures, and L2H2-6M(2)OTD, known not to disrupt the hybrid-1 structure, did not show such K(+) removal. Instead, binding of the cyclic oxazole L2H2-6M(2)OTD was accompanied by the uptake of one additional K(+). Also contrasting with telomeric G-quadruplexes, the parallel-stranded Pu24-myc G-quadruplex, to which Phen-DC3 is known to bind by end-stacking, did not undergo cation removal upon ligand binding. Our study therefore evidences that very affine ligands can induce conformational switching of the human telomeric G-quadruplexes to an antiparallel structure and that this conformational change is accompanied by removal of one interquartet cation.

Light-induced oxidation of the telomeric G4 DNA in complex with Zn(II) tetracarboxymethyl porphyrin

“…Similar conformational changes were observed for the interaction of the telomeric quadruplex with the ligands PDS, 360A and phen-DC3 (12). Authors interpreted the observed CD spectral changes in terms of a structural rearrangement of the (3+1) form to an antiparallel G4 caused by the displacement of a K + ion from the quadruplex.…”

“…G4 specific ligands either stabilize the G4 structure and/or cause certain conformational rearrangements. Binding of some bisquinolinium G4 DNA ligands (360A, Phen‐DC3 and pyridostatin) can result in the restructuring of telomeric G4 into an antiparallel two-quartets fold presumably due to the displacement of metal ions (12). The destruction of all quartets in the telomeric G4 structure in sodium or a single quartet in potassium is required for anthrathiophenedione derivative binding (13).…”

High-throughput sequencing of DNA G-quadruplex structures in the human genome

“…This suggests that it is the extent of stabilization under a given set of conditions that affects the likelihood of a G4 being detected by G4-seq. The OQs detected in the presence of PDS could also reflect the binding properties and specificity of the small molecule for G4 stabilization 25 Figure 1 A schematic of the G4-seq method. In a typical G4-seq experiment, sequencing is done twice.…”

Preparation of 6/8/11-Amino/Chloro-Oxoisoaporphine and Group-10 Metal Complexes and Evaluation of Their in Vitro and in Vivo Antitumor Activity

“…In addition, several G4 gene/oncogene promoters, such as those associated with the bcl-2 gene, have been associated with cell death/apoptosis and with diseases such as neurodegeneration, autoimmune deficiencies, and cancer13. Thus, designing and developing G4 ligands or G4s-based inhibitors are a novel potential anticancer strategy1415161718.…”

“…Some G4 ligands efficiently stabilize G-quadruplex DNA, which often leads to telomerase inhibition15161718.…”