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arXiv · 2306.04291

Phen-DC 3 Induces Refolding of Human Telomeric DNA into a Chair-Type Antiparallel G-Quadruplex through Ligand Intercalation

Anirban Ghosh·Marko Trajkovski·Marie-paule Teulade-Fichou·Valérie Gabelica·Janez Plavec
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Abstract

Human telomeric G-quadruplex DNA structures are attractive anticancer drug targets, but the target's polymorphism complicates the drug design: different ligands prefer different folds, and very few complexes have been solved at high resolution. Here we report that Phen-DC3, one of the most prominent G-quadruplex ligands in terms of high binding affinity and selectivity, causes dTAGGG(TTAGGG)3 to completely change its fold in KCl solution from a hybrid-1 to an antiparallel chair-type structure, wherein the ligand intercalates between a two-quartet unit and a pseudo-quartet, thereby ejecting one potassium ion. This unprecedented high-resolution NMR structure shows for the first time a true ligand intercalation into an intramolecular G-quadruplex.

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Anirban Ghosh, Marko Trajkovski, Marie-paule Teulade-Fichou, Valérie Gabelica, Janez Plavec. 2023-06-07. Phen-DC 3 Induces Refolding of Human Telomeric DNA into a Chair-Type Antiparallel G-Quadruplex through Ligand Intercalation. https://doi.org/10.1002/anie.202207384

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