PROBING THE INFLUENCE OF ARGININE METHYLATION ON THE MODULATION OF BIOMOLECULAR

探讨精氨酸甲基化对生物分子调节的影响

• 批准号: 7959721
• 负责人: Jason M Shearer
• 金额: $ 12.88万
• 依托单位: UNIVERSITY OF NEVADA RENO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7959721
• 关键词: Affinity; Arginine; Autistic Disorder; Binding; Biological; Biological Process; Biomedical Research; Cells; Computer Retrieval of Information on Scientific Projects Database; Computing Methodologies; DNA; DNA Binding; DNA Structure; Disease; Failure; Funding; Gene Expression; Grant; Health; Human; Institution; Lead; Malignant Neoplasms; Methylation; Modeling; Nuclear; Nucleic Acid Binding; Nucleic Acids; Peptides; Post-Translational Protein Processing; Preparation; Prion Diseases; Property; Proteins; Research; Research Personnel; Resources; Source; United States National Institutes of Health; base; cofactor; electronic structure; functional group; guanidinium; protein complex; protein protein interaction; small molecule

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Cells utilize weak biological interactions to control a multitude of biological processes. From a human health standpoint a failure in the precise control of these interactions can lead to a number of diseases ranging from cancer to prion diseases to autism. It has been shown that many proteins found in the nuclear region of cells, especially those that bind nucleic acids, undergo a post translational modification called arginine methylation. This indicates that arginine methylation is utilized to modulate gene expression, possibly by changing the binding affinity of the modified protein towards nucleic acids and other gene-expression proteins/cofactors. The magnitude of the change in the energetics and geometries of nucleic acid binding effected by arginine methylated proteins is poorly understood. The research proposed in this subproject is aimed at understanding the influence that arginine methylation has on controlling protein DNA and protein protein interactions. To these ends a number of small molecule, peptide, and protein based models that can bind 1) nucleic acids and 2) contain guanidinium-groups (the functional group of an arginine residue) will be prepared. The guanidinium group will be sequentially methylated, and the influence this has on the DNA binding properties of these model compounds, the subsequent structure of the DNA protein complex, and the strength of the DNA protein bonding interaction will be determined. In addition, high-level electronic structure computational methods will be utilized to both rationalize the results obtained from these studies and guide the preparation of the DNA-binding model compounds.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 细胞利用微弱的生物相互作用来控制多种生物过程。 从人类健康的角度来看，无法精确控制这些相互作用可能会导致多种疾病，从癌症到朊病毒疾病再到自闭症。 研究表明，细胞核区域中发现的许多蛋白质，尤其是那些结合核酸的蛋白质，都会经历称为精氨酸甲基化的翻译后修饰。 这表明精氨酸甲基化可能通过改变修饰蛋白对核酸和其他基因表达蛋白/辅因子的结合亲和力来调节基因表达。 精氨酸甲基化蛋白对核酸结合的能量学和几何学变化的程度知之甚少。本子项目提出的研究旨在了解精氨酸甲基化对控制蛋白质 DNA 和蛋白质蛋白质相互作用的影响。 为此，将制备许多基于小分子、肽和蛋白质的模型，这些模型可以结合 1) 核酸和 2) 含有胍基团（精氨酸残基的官能团）。 胍基团将依次甲基化，并确定这对这些模型化合物的 DNA 结合特性、DNA 蛋白质复合物的后续结构以及 DNA 蛋白质键合相互作用的强度的影响。 此外，高级电子结构计算方法将用于合理化这些研究获得的结果并指导 DNA 结合模型化合物的制备。