Cisplatin or cis diamminedichloroplatinum (DDP) is an inorganic anti-tumor drug. It is widely prescribed for the treatment of various tumors. Though it is very effective, it has several serious side-effects, including renal toxicity, neurotoxicity and hearing loss, among others. Cisplatin causes cell death by binding to DNA and interfering with its repair mechanism. Cisplatin is administered intravenously. It is carried through blood to the different parts of the body where it enters the cells. Inside the cell, one of the chloride ions is replaced by a molecule of water allowing the compound to bind to a nitrogen atom on a DNA nucleotide. This is followed by the second chloride ion being replaced by a water molecule as well, resulting in the platinum binding to another nucleotide.
The structure shown here is that of cisplatin bound to the N7 atoms of two adjacent guanine nucleotides on the same strand, to which cisplatin is known to bind preferentially. Once cisplatin is bound to DNA, several DNA repairing proteins are recruited to this region of the DNA. These become irreversibly bound to the DNA distorting its structure and preventing effective repair of the DNA and ultimately resulting in cell death.
Protein Data Bank (PDB)
Wing, R.M. Pjura, P. Drew, H.R. Dickerson, R.E.; "The primary mode of binding of cisplatin to a B-DNA dodecamer: C-G-C-G-A-A-T-T-C-G-C-G"; EMBO J.; (1984) 3:1201-1206 PubMed:6539674.
author: Ashwini Patil