Introduction
The intercalation of DNA and drug compounds has been studied thoroughly as a inhibitor of tumorigenesis or pathogenesis which is key in the progression of most cancers. Most intercalated ligands are aromatic compounds that bond through non-covalent interactions. In this case the nucleotide d(CGTACG) was complexed with an anthraquinone derivative. This derivative, 1,5-bis[3-(diethylamino)propionamido]anthracene-9,10-dione, provided researchers with the information needed to solve using X-Ray crystallography. Along with the structure, the important forces involved in binding were analyzed and described as heavily reliant on cations. Furthermore, the binding site seems to be specific to anthracene and similar molecules. Therefore, the potential for drug compounds to be carried by this nucleotide complex requires further research with respect to binding affinity, solubility, toxicology, and specificity with other analogues.
The 1,5-bis[3-(diethylamino)propionamido]anthracene-9,10-dione complex was studied using synchrotron radiation, which is the energy emitted from particles traveling near the speed of light, which identified ionic sites and areas of high electron density. The binding site of the drug compound is one of these high electron density areas, and was a key component in it's identification. The electron density mappings also provides insight on issues typical with the intercalation of aromatic ligands such as their degrees of freedom and the effect of counterions. The aromatic anthraquinone derivative ligand is disordered disordered in the binding site with two solvable positions which are 180 degree rotations of each other. With respect to the issue of ionic strength, DNA is a polyanion therefore positively charged counterions shielding the interactions between the DNA and the drug is worth noting. In the case of Na+, it has been resolved near the binding site of the drug. In short, this DNA/Anthraquinone derivative complex provides a potential anti-cancer drug and information about the role of positively charged ions in the intercalation of the drug compound.
Overall Structure
The 1xcs (model at right) complex is a small, simple globular DNA-drug complex, and as such lacks any traditional protein-associated structures such as secondary beta sheets or alpha helices. The complex consists of two complimentary strands of DNA. A simplified model of 1xcs is shown with the nitrogenous bases removed for clarity. The deoxyribose backbones can be followed from 5' to 3' following along each strand from blue to red. Note that the strands are antiparallel where they are (hydrogen) bonded. visualizes this bonding in the middle region of the complex, again following each strand from blue to red from 5' to 3' ends.
The 1xcs complex also binds to metal ions in more than one location, which have been shown to be important to the drug's binding ability. Different metal ions may be present, including Na(+) and Co(2+). The main metal ions sites are colored pink in scene. One other metal binding site was noted, which had the ability to bind (teal). This ability to strongly bind metal ions was also important for x-ray crystallographic purposes, as it enabled researchers to form crystals of the complex by relying on interactions between neighboring molecules' binding sites. It is also believed that the tight packing of the 1xcs complex in its solid form contributes to its ability to retain drug molecules (see "Binding Interactions").
Binding Interactions
There are three main locations where ion ligands bind to the oligonucleotide/drug complex. The key ligand is shown in pink. Its function is to close the drug cavity, holding the anthraquinone derivative in place. It can be an Na(+), Mg(2+), or Ba(2+) ion. The two other ligands, shown in cyan bind four to five nucleotides away from the drug itself. Co(2+) ions were always present at these locations in this complex and in similar complexes. Complexes that did not contain Co(2+) did not diffract. Literature states that the variable ion gives strength to the binding of the Co(2+) ions. It may be reasoned that this interaction may also behave oppositely. The binding of the Co(2+) ions may strengthen the closure of the pocket containing the drug. Co(2+) and Ba(2+) ions were found in more locations that are not shown here because they only appeared sporadically and in differing locations. Therefore, they are probably not precisely important to the function of this drug complex.
Additional Features
In , one can see that the anthraquinone derivative is located between the backbones and base pairs of DNA. The drug is squeezed or intercalated between the nucleotides . In the human body, the would also be interacting with the drug shown in black, but in order for this complex to be studied, a short segment of DNA had to be used. Consequently the gold nucleotide is involved in abnormal molecular interactions and is out of place. This intercalation interrupts the function of taq polymerase and telomerase.[2] Taq polymerase is in part responsible for the replication of DNA and consequently, cell replication. Telomeres are repeating sections of non-coding DNA that protect the ends of coding sections of DNA from degradation. Each time a cell divides, telomeres shorten. Over time, telomeres shorten to the point of disappearance, causing DNA degradation and cell death. Telomerase builds up these protective sections of DNA. Cancer is characterized as an uncontrolled rate of cell growth. By inhibiting the replication of DNA and the construction of protective telomeres, this drug serves to slow and stop cancerous cell growth.
Quiz Question 1
This complex serves to interrupt two enzymes involved in cell replication: Taq polymerase and .
A. nuclease
B. telomerase
C. ligase
D. topoisomerase
See Also
Credits
Introduction - Daniel Marco
Overall Structure - Nathaneal Park
Drug Binding Site - Annie Burton
Additional Features - Michael Beauregard
Quiz Question 1 - Jianlong Li
References
- ↑ Valls N, Steiner RA, Wright G, Murshudov GN, Subirana JA. Variable role of ions in two drug intercalation complexes of DNA. J Biol Inorg Chem. 2005 Aug;10(5):476-82. Epub 2005 Sep 23. PMID:15926069 doi:10.1007/s00775-005-0655-3
- ↑ Human Telomerase Inhibition by Regioisomeric Disubstituted Amidoanthracene-9,10-diones
Philip J. Perry,†, Anthony P. Reszka,†, Alexis A. Wood,†, Martin A. Read,†, Sharon M. Gowan,‡, Harvinder S. Dosanjh,†, John O. Trent,†,§, Terence C. Jenkins,†,‖, Lloyd R. Kelland,‡ and, and Stephen Neidle*,†
Journal of Medicinal Chemistry 1998 41 (24), 4873-4884
DOI: 10.1021/jm981067o
