Sandbox Reserved 430: Difference between revisions

{{Template:Sandbox Reserved Lynmarie Thompson}}

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===Introduction===

In this figure <scene name='Sandbox_Reserved_430/Cisplatin_intro/4'>cisplatin</scene> is <scene name='Sandbox_Reserved_430/Cisplatin_intro/7'>bound</scene> 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 <scene name='Sandbox_Reserved_430/Hmg-proetin_bound/1'>HMG-protein</scene> 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 <scene name='Sandbox_Reserved_430/Z-dna/2'>Z-DNA</scene> 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] <scene name='Sandbox_Reserved_430/Cisplatin_ligand/1'>Platination bond d(GpG)</scene>. 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. <scene name='Sandbox_Reserved_430/1a84_binding/1'>Binding</scene> 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.   

===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).