8G2N

Crystal structure of Tetrahymena thermophila G-rich DNA with novel ligand PyDH2

Summary for 8G2N

• Entry DOI: 10.2210/pdb8g2n/pdb
• Descriptor: G-rich DNA, 4,4'-{pyridine-2,6-diylbis[carbonyl-(1E)-hydrazin-2-yl-1-ylidene-(E)-methanylylidene]}bis(1-methylquinolin-1-ium), MAGNESIUM ION, ... (6 entities in total)
• Functional Keywords: g-quadruplex dna, ligand intercalation, four tetrads, dna
• Biological source: Tetrahymena thermophila
• Total number of polymer chains: 1
• Total formula weight: 8832.58

Authors

Martin, K.N.,Yatsunyk, L.A. (deposition date: 2023-02-06, release date: 2024-02-14, Last modification date: 2025-09-17)

Primary citation

Martin, K.N.,Lam, G.,Reznichenko, O.,Brunner, K.E.,Zdilla, M.J.,McCarthy, S.E.,Granzhan, A.,Yatsunyk, L.A.
Conformational Change in a Four-Tetrad DNA G-Quadruplex upon Intercalation of a Small-Molecule Ligand PyDH2.
Angew.Chem.Int.Ed.Engl., 64:e202501443-e202501443, 2025

PubMed Abstract: G-quadruplexes (G4s) are non-canonical DNA structures implicated in a number of biological processes. Small-molecule ligands can alter stability and folding of G4s, which can potentially be exploited for therapeutic purposes. In this work, we investigate the interaction of telomeric DNA fragment from Tetrahymena thermophila (TET25, 5'-G(TTGGGG)3') with a G4 ligand PyDH2 belonging to the bisquinolinium family. When alone, TET25 adopts a mixture of three conformations, with the most abundant being a four-tetrad hybrid G4. In the presence of PyDH2, surprisingly, TET25 folds into an antiparallel chair G4, with PyDH2 intercalated between G-tetrads 2 and 3, according to our crystal structure. The structure represents the second example, and the first crystallographic evidence, of ligand intercalation into a G4. In solution, the interaction of PyDH2 and TET25 leads to a number of complexes differing by G4 topology and binding stoichiometry, strong stabilization of G4 (∆T = 12.4 °C in the presence of one equiv. of PyDH2) and large hysteresis of ∼10 °C, suggesting that ligand binding and G4 folding processes are complex.

PubMed: 40403170
DOI: 10.1002/anie.202501443

Experimental method

X-RAY DIFFRACTION (1.33 Å)