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

Area of Science:

• Molecular Biology
• Structural Biology
• Medicinal Chemistry

Background:

• Quadruplex-duplex hybrids (QDHs) are DNA structures found in gene promoter regions, including the PIM1 oncogene.
• QDHs exhibit polymorphic behavior in vitro, adopting different conformations.
• Understanding QDH structure and ligand interactions is crucial for developing targeted therapies.

Purpose of the Study:

• To investigate the interaction of bis-quinolinium ligands (Phen-DC3 and 360A) with the PIM1 QDH.
• To determine the preferred QDH conformation in a cellular environment.
• To elucidate the binding modes of ligands at the quadruplex-duplex junction.

Main Methods:

• In vitro and in-cell studies using Xenopus laevis oocytes as a model system.
• High-resolution nuclear magnetic resonance (NMR) spectroscopy, including 19F-detected in-cell NMR.
• Structural determination of ligand-QDH complexes.

Main Results:

• The PIM1 QDH predominantly adopts an antiparallel conformation within Xenopus oocytes, differing from its in vitro polymorphic behavior.
• Both Phen-DC3 and 360A selectively bind to the hybrid QDH conformation, both in vitro and in cells.
• Distinct binding modes were observed: Phen-DC3 binds rigidly, while 360A exhibits dynamic reorientation at the quadruplex-duplex junction.

Conclusions:

• Ligand interactions can modulate QDH structural equilibria under physiological conditions.
• The study highlights differences between in vitro and intracellular QDH structural dynamics.
• Findings provide a basis for designing novel bis-quinolinium compounds with enhanced selectivity for the quadruplex-duplex junction.