4.6 Article

Quadruplex-Duplex Junction: A High-Affinity Binding Site for Indoloquinoline Ligands

Journal

CHEMISTRY-A EUROPEAN JOURNAL
Volume 26, Issue 70, Pages 16910-16922

Publisher

WILEY-V C H VERLAG GMBH
DOI: 10.1002/chem.202003540

Keywords

calorimetry; DNA structures; G-quadruplexes; NMR spectroscopy

Funding

  1. Deutsche Forschungsgemeinschaft [INST 292/138-1]

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A parallel quadruplex derived from the Myc promoter sequence was extended by a stem-loop duplex at either its 5 '- or 3 '-terminus to mimic a quadruplex-duplex (Q-D) junction as a potential genomic target. High-resolution structures of the hybrids demonstrate continuous stacking of the duplex on the quadruplex core without significant perturbations. An indoloquinoline ligand carrying an aminoalkyl side chain was shown to bind the Q-D hybrids with a very high affinity in the order K-a approximate to 10(7) m(-1) irrespective of the duplex location at the quadruplex 3 '- or 5 '-end. NMR chemical shift perturbations identified the tetrad face of the Q-D junction as specific binding site for the ligand. However, calorimetric analyses revealed significant differences in the thermodynamic profiles upon binding to hybrids with either a duplex extension at the quadruplex 3 '- or 5 '-terminus. A large enthalpic gain and considerable hydrophobic effects are accompanied by the binding of one ligand to the 3 '-Q-D junction, whereas non-hydrophobic entropic contributions favor binding with formation of a 2:1 ligand-quadruplex complex in case of the 5 '-Q-D hybrid.

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