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Minor-Groove Binding Drugs: Where Is the Second Hoechst 33258 Molecule?

Artikel i vetenskaplig tidskrift
Författare Louise Fornander
Lisha Wu
Martin Billeter
Per Lincoln
Bengt Nordén
Publicerad i Journal of Physical Chemistry B
Volym 117
Nummer/häfte 19
Sidor 5820-5830
ISSN 1520-6106
Publiceringsår 2013
Publicerad vid Institutionen för kemi och molekylärbiologi
Sidor 5820-5830
Språk en
Länkar dx.doi.org/10.1021/jp400418w
Ämnesord Hoechst 33258, minor groove, isothermal titration calorimetry, circular dichroism, nuclear magnetic resonance
Ämneskategorier Spektroskopi, Strukturbiologi

Sammanfattning

Hoechst 33258 binds with high affinity into the minor groove of AT-rich sequences of double-helical DNA. Despite extensive studies of this and analogous DNA binding molecules, there still remains uncertainty concerning the interactions when multiple ligand molecules are accommodated within close distance. Albeit not of direct concern for most biomedical applications, which are at low drug concentrations, interaction studies for higher drug binding are important as they can give fundamental insight into binding mechanisms and specificity, including drug self-stacking interactions that can provide base-sequence specificity. Using circular dichroism (CD), isothermal titration calorimetry (ITC), and proton nuclear magnetic resonance (1H NMR), we examine the binding of Hoechst 33258 to three oligonucleotide duplexes containing AT regions of different lengths: [d(CGCGAATTCGCG)]2 (A2T2), [d(CGCAAATTTGCG)]2 (A3T3), and [d(CGAAAATTTTCG)]2 (A4T4). We find similar binding geometries in the minor groove for all oligonucleotides when the ligand-to-duplex ratio is less than 1:1. At higher ratios, a second ligand can be accommodated in the minor groove of A4T4 but not A2T2 or A3T3. We conclude that the binding of the second Hoechst to A4T4 is not cooperative and that the molecules are sitting with a small separation apart, one after the other, and not in a sandwich structure as previously proposed.

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