Coiled-coil conformation of a pentamidine-DNA complex.
ABSTRACT The coiled-coil structure formed by the complex of the DNA duplex d(ATATATATAT)(2) with pentamidine is presented. The duplex was found to have a mixed structure containing Watson-Crick and Hoogsteen base pairs. The drug stabilizes the coiled coil through the formation of cross-links between neighbouring duplexes. The central part of the drug is found in the minor groove as expected, whereas the charged terminal amidine groups protrude and interact with phosphates from neighbouring molecules. The formation of cross-links may be related to the biological effects of pentamidine, which is used as an antiprotozoal agent in trypanosomiasis, leishmaniasis and pneumonias associated with AIDS. The DNA sequence that was used is highly abundant in most eukaryotic genomes. However, very few data are available on DNA sequences which only contain A.T base pairs.
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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.Acta Crystallographica Section D Biological Crystallography 06/2014; 70(Pt 6):1614-1621. · 7.23 Impact Factor
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ABSTRACT: Nucleic acids are the molecular targets of many clinical anticancer drugs. However, compared with proteins, nucleic acids have traditionally attracted much less attention as drug targets in structure-based drug design, partially because limited structural information of nucleic acids complexed with potential drugs is available. Over the past several years, enormous progresses in nucleic acid crystallization, heavy-atom derivatization, phasing, and structural biology have been made. Many complicated nucleic acid structures have been determined, providing new insights into the molecular functions and interactions of nucleic acids, especially DNAs complexed with small molecule ligands. Thus, opportunities have been created to further discover nucleic acid-targeting drugs for disease treatments. This review focuses on the structure studies of DNAs complexed with small molecule ligands for discovering lead compounds, drug candidates, and/or therapeutics.Medicinal Research Reviews 04/2013; · 8.13 Impact Factor
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ABSTRACT: In this paper, we present a micromechanical analysis of elastoplastic behavior of porous materials. The non-uniform transformation field analysis (NTFA) is used and the non-uniform distribution of local plastic strain in the solid matrix is taken into account. Comparisons with the classical Gurson's model and standard FEM solution are presented.Mechanics Research Communications 09/2011; 38(6):437-442. · 1.50 Impact Factor