Structural basis of bis-quinolinium ligands binding to quadruplex-duplex hybrids from PIM1 oncogene

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Authors	GHOSH Anirban HARNOŠ Jakub STADLBAUER Petr SPONER Jiri ZIVKOVIC Martina Lenarcic TRANTÍREK Lukáš
Year of publication	2025
Type	Article in Periodical
Magazine / Source	Nucleic Acids Research
MU Faculty or unit	Central European Institute of Technology
Citation
web	https://academic.oup.com/nar/article/53/17/gkaf894/8251892
Doi	https://doi.org/10.1093/nar/gkaf894
Keywords	MOLECULAR-DYNAMICS SIMULATION; SPARTICLE MESH EWALD; AMBER FORCE-FIELD; NUCLEIC-ACIDS; NMR-SPECTROSCOPY; DNA; SUPPRESSION; INTEGRATION; EXCITATION; PROMOTERS
Attached files	2529118.pdf
Description	Our study investigates the interaction of two bis-quinolinium ligands, Phen-DC3 and 360A, with the quadruplex–duplex hybrid (QDH) derived from the promoter region of the PIM1 oncogene. While the QDH is polymorphic in vitro, with a hybrid and antiparallel conformation, we demonstrate that it predominantly adopts the antiparallel conformation within the intracellular environment of Xenopus laevis oocytes (eukaryotic model system). Notably, both ligands selectively bind to the hybrid QDH conformation in vitro and in a cellular context. High-resolution nuclear magnetic resonance (NMR) structures of the complexes between the hybrid QDH and the ligands reveal distinct binding modes at the quadruplex–duplex (Q-D) junction. Specifically, Phen-DC3 binds rigidly, while 360A dynamically reorients between two positions. Our findings provide a crucial paradigm highlighting the differences in structural equilibria involving QDH in vitro compared to its behavior in the intracellular space. They also underscore the potential to modulate these equilibria under native-like conditions through ligand interactions. The observed differences in the binding of Phen-DC3 and 360A lay the groundwork for designing next-generation bis-quinolinium compounds with enhanced selectivity for the Q-D junction. Methodologically, our study illustrates the potential of 19F-detected in-cell NMR methodology for screening interactions between DNA targets and drug-like molecules under physiological conditions.
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