Binding properties and DNA sequence-specific recognition of two bithiazole-linked netropsin hybrid molecules
| Autor: | D Mrani, Raymond Houssin, Lown Jw, Jean Louis Imbach, Pierre Colson, Claude Houssier, Michael J. Waring, Jean-Pierre Hénichart, Gilles Gosselin, Christian Bailly |
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| Rok vydání: | 1992 |
| Předmět: |
Stereochemistry
Molecular Sequence Data Restriction Mapping Biology Linear dichroism Biochemistry Bleomycin Structure-Activity Relationship chemistry.chemical_compound Moiety Peptide bond A-DNA Binding Sites Deoxyribonucleases Base Sequence Molecular Structure DNase-I Footprinting Netropsin DNA Footprinting DNA-Binding Proteins Thiazoles Oligodeoxyribonucleotides chemistry Nucleic Acid Conformation |
| Zdroj: | Biochemistry. 31:8349-8362 |
| ISSN: | 1520-4995 0006-2960 |
| DOI: | 10.1021/bi00150a032 |
| Popis: | We report the DNA binding properties of two hybrid molecules which result from the combination of the DNA sequence-specific minor groove ligand netropsin with the bithiazole moiety of the antitumor drug bleomycin. The drug-DNA interaction has been investigated by means of electric linear dichroism (ELD) spectroscopy and DNase I footprinting. In compound 1 the two moieties are linked by a flexible aliphatic tether while in compound 2 the two aromatic ring systems are directly coupled by a rigid peptide bond. The results are consistent with a model in which the netropsin moiety of compound 1 resides in the minor groove of DNA and where the appended bithiazole moiety is projected away from the DNA groove. This monocationic hybrid compound has a weak affinity for DNA and shows a strict preference for A and T stretches. ELD measurements indicate that in the presence of DNA compound 2 has an orientation typical of a minor groove binder. Similar orientation angles were measured for netropsin and compound 2. This ligand which has a biscationic nature tightly binds to DNA (Ka = 6.3 x 10(5) M-1) and is mainly an AT-specific groove binder. But, depending on the nature of the sequence flanking the AT site first targeted by its netropsin moiety, the bithiazole moiety of 2 can accommodate various types of nucleotide motifs with the exception of homooligomeric sequences. As evidenced by footprinting data, the bithiazole group of bleomycin acts as a DNA recognition element, offering opportunities to recognize GC bp-containing DNA sequences with apparently a preference (although not absolute) for a pyrimidine-G-pyrimidine motif. Thus, the bithiazole unit of bleomycin provides an additional anchor for DNA binding and is also capable of specifically recognizing particular DNA sequences when it is appended to a strongly sequence selective groove binding entity. Finally, a model which schematizes the binding of compound 2 to the sequence 5'-TATGC is proposed. This model readily explains the experimentally observed specificity of this netropsin-bithiazole conjugate. |
| Databáze: | OpenAIRE |
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