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Cisplatin-DNA complex- 1a84
Introduction
In this figure is to a 12 base pair double stranded DNA, creating a 49° bend with an overall helix bend of 78°. This bend in the DNA is crucial to cisplatin’s role as an anticancer drug. Cisplatin, cis-PtCl2(NH3)2, is a chemotherapy drug, administered intravenously, used in the treatment of various types of cancer. This platinum-based drug acts in vivo by binding to two consecutive adjacent guanine bases in DNA. The binding of cisplatin bends the DNA, allowing for HMG-protein to bind. Once the is bound, de-stacking of the nucleotide base pairs occurs, which in turn kinks the DNA. With the HMG-protein bound to the DNA, the cell cannot properly repair the DNA, leading to apoptosis.
Overall Structure
The original view shows a double stranded DNA helix and the cisplatin ligand. This molecule is in its Z configuration which means it has a left handed helix. It is much more rare than the common B-DNA which is right handed. The sugar-phosphate backbone has a zigzag pattern due to the alternate stacking of bases in anti-conformation and syn conformation. In Z-DNA only a minor groove is present and the major groove is absent. This DNA form is thought to play a role in the regulation of gene expression, DNA processing events and/or genetic instability.[2] . The cisplatin ligand is a cis-diammineplatinum molecule, which is a platinum atom attached to two N7 nitrogen atoms, each apart of a guanine base pair, and two NH3 molecules attached to the other side. They attach to the 6 and 7 guanine base pairs which links the two bases together and alters the bend in the helix by 49 degrees. The guanine still pair with the 18 and 19 cytosine bases. There are no alpha helixs or beta strands because cisplatin works with DNA and not on proteins.
Binding Interactions
As described above, the cisplatin ligand binds to the N7 atoms of the adjacent G6 and G7 guanine bases in a strand of DNA. The N7 atoms are bound to the platinum atom in the ligand, creating a bend in the helix towards the guanine bases of 49 degrees. The resulting platination also causes the duplex to unwind by approximately 25 degrees at the site of platination from the base pair T8-A17 to T5-A20. These distortions in the duplex allow the minor groove opposite the platinum to be opened to 9.0-12 angstroms, making it shallow and wide.
HMG-domain proteins (High-mobility group) bind to recognition sequences found in the minor groove. The bend in DNA caused by cisplatin leaves the minor groove more vulnerable and open for recognition by HMG-domain proteins. Since the expression of these proteins are correlated to tumor cells, the recognition of them by cisplatin-bound DNA could lead to a therapy of cancerous tumors.
Additional Features
Structural studies of cisplatin-modified DNA are underway in hope to find a significant correlation between cisplatin distorted DNA and its ability to bind to high mobility group proteins (HMG proteins).
HMG proteins are responsible for many actions within the cell such as transcription, replication and DNA repair. Studies show that over/under expression of these proteins may be the cause of tumors.
HMG proteins bind to the minor groove of the DNA duplex where their recognition sequences are located. Cisplatin is known to cause a large helix bend of DNA as well as the extension of the minor groove width. This opening of the minor groove allows the recognitions of HMG domain proteins.
The positioning of this bend is over a length of 5 base pairs from C4-G21 to T8-A17. This the results in a 49 degree roll of the G6*pG7* guanine-guanine interaction causing a helical bend of 78 degrees.
This deformation of the DNA duplex can be compared to that cause by HMG proteins, LEF-1 and hSRY . The LEF-1 structure is bent by 117 degrees and the hSRY complex is bent by 70-80 degrees. The overall global deformation of both the LEF-1 and hSRY highly resemble that if the cisplatin bound duplex. This comparison of LEF-1 and hSRY DNA to cisplatin-modified DNA brings structural evidence that cisplatin –modified DNA may signal the recognition of HMG protiens.
Credits
Introduction - Gina Lein
Overall Structure - Greg Keohane
Drug Binding Site - Louis Pires
Additional Features - Nicole Hofstetter
References
1.↑ 2.0 2.1 2.2 2.3 2.4 2.5 Wang G, Vasquez KM. Z-DNA, an active element in the genome. Front Biosci. 2007 May 1;12:4424-38. PMID:17485386
