In and out of the minor groove: interaction of an AT-rich DNA with the drug CD27.

Francisco J Acosta-Reyes,Juan A Subirana,Christophe Dardonville,Harry P De Koning,Manal Natto,J Lourdes Campos

doi:10.1107/s139900471400697x

Abstract

The DNA of several pathogens is very rich in AT base pairs. Typical examples include the malaria parasite Plasmodium falciparum and the causative agents of trichomoniasis and trypanosomiases. This fact has prompted studies of drugs which interact with the minor groove of DNA, some of which are used in medical practice. Previous studies have been performed almost exclusively with the AATT sequence. New features should be uncovered through the study of different DNA sequences. In this paper, the crystal structure of the complex of the DNA duplex d(AAAATTTT)2 with the dicationic drug 4,4'-bis(imidazolinylamino)diphenylamine (CD27) is presented. The drug binds to the minor groove of DNA as expected, but it shows two new features that have not previously been described: (i) the drugs protrude from the DNA and interact with neighbouring molecules, so that they may act as cross-linking agents, and (ii) the drugs completely cover the whole minor groove of DNA and displace bound water. Thus, they may prevent the access to DNA of proteins such as AT-hook proteins. These features are also expected for other minor-groove binding drugs when associated with all-AT DNA. These findings allow a better understanding of this family of compounds and will help in the development of new, more effective drugs. New data on the biological interaction of CD27 with the causative agent of trichomoniasis, Trichomonas vaginalis, are also reported.

Highlights

Enormous progress has been achieved in the past in the study of small-molecule ligands that have affinity for the DNA minor groove, as recently reviewed by Sheng et al (2013)
We describe a completely different DNA interaction behaviour of CD27: the compound completely covers the minor groove of the two A-tracts of the oligonucleotide d(AAAATTTT)2
We have found that the CD27 molecule completely covers the entire minor groove of the DNA duplexes

Summary

Introduction

Enormous progress has been achieved in the past in the study of small-molecule ligands that have affinity for the DNA minor groove, as recently reviewed by Sheng et al (2013). More complex types of drug binding to DNA have been reviewed by Boer et al (2009). Dervan and coworkers have carried out an extensive series of studies (Sheng et al, 2013; Chenoweth & Dervan, 2009) aimed at developing ligands that recognize specific DNA sequences. Some intercalating drugs favour binding through the minor groove (Niyazi et al, 2012). The main group of studies has concentrated on the interaction of different drugs with AT-rich DNA regions, mainly with the Dickerson–Drew dodecamer d(CGCGAATTCGCG), which provides crystals with high resolution suitable for X-ray analysis.

Methods

Results

Conclusion