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Delta chirality ruthenium 'light-switch' complexes can bind in the minor groove of DNA with five different binding modes.

ABSTRACT: [Ru(phen)2(dppz)]2+ has been studied since the 1990s due to its 'light-switch' properties. It can be used as a luminescent DNA probe, with emission switched on through DNA binding. The luminescence observed is dependent on the solvent accessibility of the pyrazine nitrogen atoms, and therefore is sensitive to changes in both binding site of the cation and chromophore orientation. The compound is also chiral, and there are distinct differences between the enantiomers in terms of the emission behaviour when bound to a variety of DNA sequences. Whilst a number of binary DNA-complex X-ray crystal structures are available, most include the ? enantiomer and there is very little structural information about binding of the ? enantiomer. Here, we present the first X-ray crystal structure of a ? enantiomer bound to well-matched DNA, in the absence of the other, ? enantiomer. We show how the binding site observed here can be related to a more general pattern of motifs in the crystallographic literature and propose that the ? enantiomer can bind with five different binding modes, offering a new hypothesis for the interpretation of solution data.

SUBMITTER: Hall JP

PROVIDER: S-EPMC5100598 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Delta chirality ruthenium 'light-switch' complexes can bind in the minor groove of DNA with five different binding modes.

Hall James P JP Keane Páraic M PM Beer Hanna H Buchner Katrin K Winter Graeme G Sorensen Thomas L TL Cardin David J DJ Brazier John A JA Cardin Christine J CJ

Nucleic acids research 20160905 19

[Ru(phen)<sub>2</sub>(dppz)]<sup>2+</sup> has been studied since the 1990s due to its 'light-switch' properties. It can be used as a luminescent DNA probe, with emission switched on through DNA binding. The luminescence observed is dependent on the solvent accessibility of the pyrazine nitrogen atoms, and therefore is sensitive to changes in both binding site of the cation and chromophore orientation. The compound is also chiral, and there are distinct differences between the enantiomers in term ...[more]

PMID: 27599841

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Project description:The HIV genome is rich in A but not G or U and deficient in C. This nucleotide bias controls HIV phenotype by determining the highly unusual composition of all major HIV proteins. The bias is also responsible for the high frequency of narrow DNA minor groove sites in the double-stranded HIV genome as compared to cellular protein coding sequences and the bulk of the human genome. Since drugs that bind in the DNA minor groove disrupt nucleosomes on sequences that contain closely spaced oligo-A tracts which are prevalent in HIV DNA because of its bias, it was of interest to determine if these drugs exert this selective inhibitory effect on HIV chromatin. To test this possibility, nucleosomes were reconstituted onto five double-stranded DNA fragments from the HIV-1 pol gene in the presence and in the absence of several minor groove binding drugs (MGBDs). The results demonstrated that the MGBDs inhibited the assembly of nucleosomes onto all of the HIV-1 segments in a manner that was proportional to the A-bias, but had no detectable effect on the formation of nucleosomes on control cloned fragments or genomic DNA from chicken and human. Nucleosomes preassembled onto HIV DNA were also preferentially destabilized by the drugs as evidenced by enhanced nuclease accessibility in physiological ionic strength and by the preferential loss of the histone octamer in hyper-physiological salt solutions. The drugs also selectively disrupted HIV-containing nucleosomes in yeast as revealed by enhanced nuclease accessibility of the in vivo assembled HIV chromatin and reductions in superhelical densities of plasmid chromatin containing HIV sequences. A comparison of these results to the density of A-tracts in the HIV genome indicates that a large fraction of the nucleosomes that make up HIV chromatin should be preferred in vitro targets for the MGBDs. These results show that the MGBDs preferentially disrupt HIV-1 chromatin in vitro and in vivo and raise the possibility that non-toxic derivatives of certain MGBDs might serve as a novel class of anti-HIV agents.

Dataset Information

Delta chirality ruthenium 'light-switch' complexes can bind in the minor groove of DNA with five different binding modes.

Publications

Delta chirality ruthenium 'light-switch' complexes can bind in the minor groove of DNA with five different binding modes.

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