PHYSICAL STUDIES OF DRUG AND PROTEIN-DNA INTERACTIONS

药物和蛋白质-DNA 相互作用的物理研究

• 批准号: 3287062
• 负责人: MARY D BARKLEY
• 金额: $ 14.94万
• 依托单位: LOUISIANA STATE UNIV A&M COL BATON ROUGE
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-09-01 至 1992-04-06
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3287062
• 关键词: DNA; adenosine deaminase; antineoplastic antibiotics; cations; chemical addition; circular dichroism; conformation; drug interactions; fluorescence polarization; fluorescent dye /probe; light scattering; molecular rearrangement; nuclear magnetic resonance spectroscopy; nucleic acid sequence; nucleic acid structure; nucleobase; protein structure; synthetic nucleic acid; transferase

The proposed research involves fluorescence studies of drug-DNA adducts and proteins. The complicated emissions from these systems will be resolved by global analysis of time-resolved fluorescence decay data obtained under different experimental conditions. The interaction of pyrrolo(1,4)- bensodiazepine antitumor antibiotics with DNA will be characterized using spectroscopic and hydrodynamic techniques. The effects of DNA sequence and conformation on the covalent drug-DNA interaction will be investigated in fluorescence and CD experiments with synthetic and natural DNAs. The effects of drug binding on DNA solution conformation will be determined by static and dynamic light scattering. These antibiotics provide a new fluorescent probe for rapid internal motions in the DNA double helix. DNA dynamics will be studied by fluorescence depolarization measurements in the time as well as frequency domains. The emission anisostropy data for covalent drug-DNA adducts will be analyzed according to the predicted nonexponential decay law. The effects on the dynamics of factors influencing DNA structure will be examined. Two enzymes involved in nucleic acid metabolism will be investigated by steady-state and time-resolved fluorescence measurements. The interactions of terminal transferase with monomer and polymer substrates and of adenosine deaminase with ground-state and transition-state inhibitors will be characterized. The effects of ligand binding on protein conformation nand dynamics will be determined. The above research is aimed at elucidation of the role of DNA flexibility in biological function. It also offers insight into the mechanism of action of antitumor antibiotics and of enzymes important in human leukemia.

拟议的研究涉及药物-DNA加合物的荧光研究和 蛋白质。这些系统的复杂排放将通过以下方式解决 时间分辨荧光衰变数据的全球分析 不同的实验条件。吡咯并(1，4)-的相互作用 含DNA的苯二氮卓类抗肿瘤抗生素将用 光谱和流体动力学技术。DNA序列和DNA序列的影响 共价药物-DNA相互作用的构象将在 用合成DNA和天然DNA进行荧光和CD实验。这个 药物结合对DNA溶液构象的影响将由 静态和动态光散射。这些抗生素提供了一种新的 用于DNA双螺旋中快速内部运动的荧光探针。脱氧核糖核酸 动力学将通过荧光去偏振测量来研究 时间域和频域。的发射各向异性数据 共价药物-DNA加合物将根据预测进行分析 非指数衰减定律。影响因素动态变化的因素 我们将研究影响DNA结构的因素。参与其中的两种酶 核酸新陈代谢的研究将通过稳态和 时间分辨荧光测量。终端之间的相互作用 具有单体和聚合物底物的转移酶以及腺苷脱氨酶 对基态和过渡态的缓蚀剂进行了表征。 配基结合对蛋白质构象和动力学的影响将是 下定决心。上述研究旨在阐明DNA的作用 生物功能上的灵活性。它还提供了对 抗肿瘤抗生素及其重要酶的作用机制 人类白血病。