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Genome-wide Mapping of Drug-DNA Interactions in Cells with COSMIC (Crosslinking of Small Molecules to Isolate Chromatin)
Published on: January 20, 2016
Indirect effects modulating the interaction between DNA and a cytotoxic bisnaphthalimide reveal a two-step binding
Luis González-Bulnes1, José Gallego
1Centro de Investigacion Principe Felipe, Avda. Autopista del Saler 16, 46012 Valencia, Spain.
Journal of the American Chemical Society
|May 20, 2009
Summary
DNA sequence flanking regions influence cytotoxic drug elinafide binding. Unfavorable sequences with A-tracts hinder drug intercalation, affecting DNA-drug interactions and stability.
Area of Science:
- Molecular Biology
- Biochemistry
- Structural Biology
Background:
- DNA sequence-specific structural and dynamic properties are crucial for biological processes involving DNA recognition.
- The cytotoxic agent elinafide targets preferred bisintercalation sites on double-helical DNA.
Purpose of the Study:
- To investigate how DNA sequences, not directly interacting with elinafide, modulate its binding.
- To understand the influence of flanking sequences on elinafide's interaction with DNA bisintercalation sites.
Main Methods:
- Nuclear Magnetic Resonance (NMR) spectroscopy
- Surface Plasmon Resonance (SPR)
- UV thermal denaturation experiments
Main Results:
- Two superimposed interaction processes were observed: ligand binding and ring intercalation.
- Flanking sequences, via indirect readout, influence both processes, particularly intercalation.
- A-tracts in flanking sequences oppose naphthalimide ring intercalation, reducing thermal stability and altering binding thermodynamics.
Conclusions:
- Sequence-dependent indirect readout significantly impacts elinafide-DNA interactions.
- Specific DNA sequences, like those with A-tracts, can impede drug intercalation.
- Elinafide complexes with unfavorable sequences exhibit weakened stacking interactions and increased dynamics.
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