The G-quadruplex (GQ) is a non-canonical DNA structure formed by G-rich DNA sequences found throughout the human genome. Stable GQs at telomeres are suggested to inhibit telomerase activity and disrupt telomeric structure, leading to cancer cell apoptosis. In this work, we investigate the interaction of a G-rich sequence from the Tetrahymena thermophila telomere, 5’-GGGTTGGGTTGGGTTGGG-3’ (T1), with a water-soluble porphyrin, N-methyl mesoporphyrin IX (NMM). UV-vis and fluorescence titrations revealed a 1:1 binding stoichiometry with an impressively tight binding constant, Ka, of 50 ± 20 μM-1 (Kd ≈ 20 nM). Isothermal titration calorimetry demonstrated that the binding interaction is enthalpically-driven and thermodynamically favorable (ΔH = -17 ± 3 kcal/mol and ΔG = -10 ± 3 kcal/mol). Job plot confirmed the 1:1 binding stoichiometry in a model-independent manner. We present the crystal structure of the GQ-NMM complex solved at 2.34 Å. This structure reveals that the DNA forms a dimer of parallel GQs bound at both ends to NMM via end-stacking interactions, supporting the 1:1 binding stoichiometry observed in biophysical studies. Our work provides invaluable details about GQ-ligand binding interactions both at the atomic level and through biophysical characterization, thereby informing GQ-targeting anticancer drug design.

Crystal structure and biophysical studies of G-quadruplex DNA in complex with a tightly binding porphyrin ligand

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.