Zinc Fingers as Templates for Metal Complex Interactions

锌指作为金属络合物相互作用的模板

• 批准号: 1413189
• 负责人: Nicholas Farrell
• 金额: $ 49.5万
• 依托单位: Virginia Commonwealth University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1413189&HistoricalAwards=false
• 关键词: Zinc; Fingers; Templates; Metal; Complex

DNA is recognized with exquisite specificity by a group of proteins collectively known as zinc fingers. The DNA-zinc finger interaction has important biological consequences, for example when cells divide or viruses multiply. The proposed experiments will explore a newly discovered means for disrupting the interaction using metal containing compounds (specifically platinum) discovered in the laboratory of the principal investigator. Future research will be conducted to understand and control this property for the development of new medicines like anti-viral (especially HIV) compounds. The approach will be both experimental (chemical and biological) and theoretical (computational). The project represents an excellent example of the linkage between basic research and discovery on one hand, and important societal benefits on the other. The research project will also be part of an international collaboration exposing graduate students to the subject, and to cross-cultural experiences.With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Dr. Nicholas Farrell from Virginia Commonwealth University to characterize reactions of zinc finger proteins by the systematic study of steric and electronic effects of functionalized coordination compounds on the kinetics and thermodynamics of zinc displacement and disruption of protein structure and function. A specific focus will be on the HIV NCp7 nucleocapsid protein (NC), and the mechanism of platinum-metal nucleobases as nucleocapsid-nucleic acid antagonists through interruption of the NC-RNA(DNA) interaction will be examined. The factors affecting selective "non-covalent" ligand-biomolecule recognition through enhanced pi-pi; stacking between metallated nucleobases and the tryptophan-containing nucleocapsid will be examined. Secondly, such recognition can lead to formation of the "covalent" metal-thiolate bond and subsequent zinc ejection. We will explore the analogy of weak "organic" and "inorganic" electrophiles to design specific interactions differentiating the distinct Cys2His2, Cys3His and Cys4 zinc finger-binding sites.

DNA被一组蛋白质识别，这些蛋白质统称为锌指。 DNA-锌指相互作用具有重要的生物学后果，例如当细胞分裂或病毒繁殖时。 拟议的实验将探索一种新发现的方法，使用主要研究者实验室中发现的含金属化合物（特别是铂）破坏相互作用。 未来的研究将进行，以了解和控制这种特性，用于开发新的药物，如抗病毒（特别是艾滋病毒）化合物。 该方法将是实验（化学和生物）和理论（计算）。 该项目是基础研究和发现与重要的社会效益之间联系的一个很好的例子。 该研究项目也将成为国际合作的一部分，让研究生接触到这一主题，并获得跨文化体验。化学部的生命过程化学计划正在资助弗吉尼亚联邦大学的尼古拉斯·法雷尔博士，通过系统地研究功能化配位化合物对动力学的空间和电子效应来表征锌指蛋白质的反应，锌置换热力学和蛋白质结构和功能的破坏。 一个具体的重点将是对HIV NCp 7核衣壳蛋白（NC），并通过中断NC-RNA（DNA）相互作用的核衣壳核酸拮抗剂的铂金属核碱基的机制将被检查。影响选择性的“非共价”配体生物分子识别，通过增强的π-π的因素;金属化的核碱基和含Dahan的核衣壳之间的堆叠将被检查。其次，这种识别可以导致形成“共价”金属-硫醇盐键和随后的锌排出。我们将探索弱的“有机”和“无机”亲电体的类比，以设计区分不同的Cys 2 His 2，Cys 3 His和Cys 4锌指结合位点的特定相互作用。