Phen‐DC₃ Induces Refolding of Human Telomeric DNA into a Chair‐Type Antiparallel G‐Quadruplex through Ligand Intercalation

Abstract

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‐DC 3 , 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.