Ligand-induced conformational changes with cation ejection upon binding to human telomeric DNA G-quadruplexes.

Area of Science:

• Biochemistry
• Molecular Biology
• Medicinal Chemistry

Background:

• Human telomeric DNA G-quadruplexes exhibit structural polymorphism under physiological conditions.
• Ligand-induced conformational switching of G-quadruplexes is often neglected in computational modeling.
• Understanding these dynamics is crucial for developing targeted therapies.

Purpose of the Study:

• To investigate the impact of potent G-quadruplex ligands on telomeric DNA G-quadruplex conformation.
• To determine if ligand binding induces specific structural changes and associated cation dynamics.
• To compare the effects of different ligands on various G-quadruplex structures.

Main Methods:

• Circular dichroism spectroscopy to assess DNA conformation.
• Electrospray mass spectrometry to analyze potassium ion coordination.
• Binding studies with established and control G-quadruplex ligands.

Main Results:

• Potent ligands (360A, Phen-DC3, pyridostatin) induced a switch to an antiparallel G-quadruplex structure.
• This conformational change was accompanied by the removal of one potassium ion.
• Control ligands did not induce cation removal, with one ligand even increasing potassium uptake.

Conclusions:

• High-affinity ligands can induce significant conformational switching in human telomeric G-quadruplexes.
• Ligand-mediated cation removal is a key feature of this conformational change.
• These findings are vital for the rational design of G-quadruplex-targeting drugs.