INTERACTION OF CELLULAR PROTEINS WITH PLATINATED DNA

细胞蛋白质与铂化 DNA 的相互作用

• 批准号: 2429884
• 负责人: ANDREW K GELASCO
• 金额: $ 2.86万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-06-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/2429884
• 关键词: DNA binding protein; X ray crystallography; antineoplastics; biochemistry; chemical binding; cis platinum compound; intermolecular interaction; molecular biology; molecular site; nonhistone nucleoprotein; nuclear magnetic resonance spectroscopy; oligonucleotides; protein structure; site directed mutagenesis

Cisplatin and related inorganic platinum complexes are known to be potent anti-cancer drugs, particularly effective against ovarian and testicular cancers. It has been demonstrated that the Pt compound binds covalently to purine nucleotides of DNA. Recent work has indicated that the Pt-modified DNA is protected from normal cellular repair mechanisms by a class of proteins, known as HMG domain proteins. The HMG protein has a DNA binding site that is specific for bends and kinks in the DNA, like those caused by platinum binding. This interaction contributes greatly to the toxicity of Pt drugs toward tumor cells. We will explore the interaction of HMG domain proteins with platinated DNA and synthetic oligonucleotides through distance-dependent NMR studies and through site-directed mutagenesis of the binding domain. The elucidation of the mode of interaction of these proteins with modified DNA provides direction for the production of new inorganic anticancer drugs that can take advantage of the binding affinity of the domain. This can also lead to the use of new anticancer therapy using both Pt chemotherapy and directed gene therapy, to produce modified protein at the site.

顺铂和相关的无机铂络合物已知 有效的抗癌药物，特别有效地抵抗卵巢和 睾丸癌。 已经证明PT化合物结合 共价为DNA的嘌呤核苷酸。最近的工作表明 PT修饰的DNA受到正常细胞修复机制的保护 通过一类蛋白质，称为HMG结构蛋白。 HMG蛋白 具有DNA结合位点，该结合位点特异于DNA中的弯曲和扭结 就像铂结合引起的那些一样。 这种互动有助于 PT药物对肿瘤细胞的毒性极大。 我们将探索 HMG结构蛋白与铂DNA和合成的相互作用 通过距离依赖性NMR研究以及通过 结合结构域的位置定向诱变。 阐明 这些蛋白质与修饰DNA的相互作用方式提供了 生产新的无机抗癌药物的方向 利用域的结合亲和力。 这也可以 导致使用PT化学疗法和 定向基因治疗，在该地点产生改良的蛋白质。