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Updated: Nov 21, 2025

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Ligand Binding to Dynamically Populated G-Quadruplex DNA.

Mikayel Aznauryan1,2, Sofie Louise Noer1, Camilla W Pedersen1

  • 1Department of Chemistry and iNANO center, Aarhus University, Gustav Wieds Vej 14, 8000, Aarhus, Denmark.

Chembiochem : a European Journal of Chemical Biology
|January 15, 2021
PubMed
Summary
This summary is machine-generated.

Small-molecule ligands stabilize G-quadruplex (G4) DNA by inducing formation and trapping dynamic structures, not just binding pre-folded G4s. This reveals new mechanisms for therapeutic G4 stabilization.

Keywords:
G-quadruplexPhen-DC3dynamicsligand bindingsmFRET

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Area of Science:

  • Molecular Biology
  • Biophysics
  • Medicinal Chemistry

Background:

  • G-quadruplex (G4) structures are promising therapeutic targets due to their role in various cellular processes.
  • G4 formation is dynamic and polymorphic, influenced by cations and sequence.
  • Small-molecule ligands can bind and stabilize G4s, but their precise binding mechanisms are not fully understood.

Purpose of the Study:

  • To investigate the mechanism of ligand binding to dynamically populated human telomere G-quadruplex DNA.
  • To understand how ligands like Phen-DC3 interact with G4 structures of varying stability and cation environments.
  • To elucidate the role of ligand binding in G4 folding dynamics and conformational changes.

Main Methods:

  • Single-molecule Förster Resonance Energy Transfer (smFRET) microscopy.
  • Ensemble FRET and Circular Dichroism (CD) spectroscopies.
  • Utilized various cations to modulate G4 polymorphism and folding dynamics.

Main Results:

  • Phen-DC3 binds to pre-folded G4 structures and can also induce G4 formation from unfolded single strands.
  • Ligand binding to dynamic G4s triggers significant conformational redistributions.
  • These redistributions are driven by ligand-induced G4 folding and trapping of transient G4 conformations.

Conclusions:

  • Ligand-induced stabilization of G4 DNA does not solely rely on the presence of pre-existing, stable G4 structures.
  • Ligands can actively promote G4 formation and stabilize transient states, offering new therapeutic strategies.
  • Understanding these dynamic mechanisms is crucial for developing effective G4-targeting therapeutics.