Conformational Change in a Four‐Tetrad DNA G‐Quadruplex upon Intercalation of a Small‐Molecule Ligand PyDH2
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)<sub>4-</sub>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<sub>m</sub> = 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.
Authors
- Kailey N. Martin (ORCID: https://orcid.org/0000-0001-6025-262X)
- Anton Granzhan (ORCID: https://orcid.org/0000-0002-0424-0461)
- Liliya A. Yatsunyk (ORCID: https://orcid.org/0000-0003-3946-0939)
- Michael J. Zdilla (ORCID: https://orcid.org/0000-0003-0212-2557)
- Karl Brünner (ORCID: https://orcid.org/0000-0002-5979-4162)
- Sawyer McCarthy (ORCID: https://orcid.org/0000-0002-1063-1784)
- Oksana Reznichenko (ORCID: https://orcid.org/0000-0002-2339-4802)
- Gwendolyn Lam
Institutions
- Swarthmore College (US)
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Université Paris-Saclay (FR)
- Chimie et Modélisation pour la Biologie du Cancer (FR)
- Institut Curie (FR)
- Temple University (US)
Publication Details
- Journal
- Angewandte Chemie International Edition
- Published
- 2025-05-22
- DOI
- https://doi.org/10.1002/anie.202501443
- Citations
- 2
- Primary Topic
- DNA and Nucleic Acid Chemistry
- Type
- article
- Field-Weighted Citation Impact
- 1.61
Funders
- National Science Foundation
- U.S. Department of Energy
- Swarthmore College
- Agence Nationale de la Recherche
- National Institutes of Health
- Office of Science
- National Institute of General Medical Sciences
- Division of Chemistry
- Basic Energy Sciences
- Biological and Environmental Research
- Office of Research Infrastructure Programs, National Institutes of Health
- Argonne National Laboratory
- Brookhaven National Laboratory