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

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.