DNA Structural Study Through Cisplatin Binding
Yi Ran (Tiger) Xu
St George's School
Floor Location : S 055 H
Cisplatin is a well-known chemotherapeutic drug for several types of human cancers, such as bladder, ovarian, and testicular cancers. Cisplatin takes effect by crosslinking the purine bases of human DNA in carcinogenic cells and interfering with their DNA replication, leading to their Apoptosis. Though the advantages of Cisplatin as a chemotherapeutic drug are widely recognized, Cisplatin also has a wide range of side effects including bone marrow suppression, hearing problems, kidney problems, vomiting and so on. Yet, the causes of these side effects cannot be explained because the conformational alteration of DNA after crosslinking with Cisplatin is unknown. Thus, further structural knowledge is crucial to better understand the mechanism of this molecule. Currently, x-ray crystallography is the most powerful technology to obtain high-resolution 3D structures of biological macromolecules. In my experiment, Cisplatin will co-crystallize with purified DNA. The resulting crystal structure obtained through x-ray crystallography provides me with detailed structural information about the Cisplatin molecule. I aim to find whether the crystallization pattern of Cisplatin-DNA complex will change based on varying concentrations of Cisplatin to DNA in the complex, and whether the Cisplatin binding will generate DNA conformational change. Through my experiment, I found that Cisplatin binds to DNA exclusively on the 7- position of Guanine. When I increased the Cisplatin concentration, more Cisplatin molecules were observed to bind with the DNA, but the binding site was still only limited to the 7-position of Guanine. In addition, upon binding, no obvious increase in the degree of conformational change was observed as I increased the concentration of Cisplatin. In the future, with the high resolution structures in hand, it is possible to further optimize the Cisplatin drug through chemical modifications such as lowering its toxicity and improving its effectiveness, potentially generating an upgraded Platinum drug with higher effectiveness.