Structural studies of chromatin complexes

染色质复合物的结构研究

• 批准号: 10263200
• 负责人: SONG TAN
• 金额: $ 57.04万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10263200
• 关键词: Address; Biochemical; Cells; Chromatin; Complement; Complex; Cryoelectron Microscopy; Crystallization; DNA; Data; Development; Disease; Enzymes; Eukaryotic Cell; Gene Expression; Genetic; Genomics; Histones; Malignant Neoplasms; Multienzyme Complexes; Nucleosomes; Physiological; Post-Translational Protein Processing; Proteins; Roentgen Rays; Structure; genetic information; histone modification; human disease; new therapeutic target; novel strategies; small molecule; stem cells; three dimensional structure

Project Summary/Abstract The post-translational modification of histone proteins is now established as an important mechanism for regulating gene expression in eukaryotic cells. However, a structural and mechanistic understanding of how the histone modification enzymes function on their nucleosome substrate is lacking. This shortcoming limits interpretation of the wealth of genetic, genomic and biochemical data available, and it hampers development of new therapeutics that target the many chromatin enzymes associated with human diseases including cancer. We are focused on addressing these deficiencies through structure determination of histone modification enzymes bound to their physiological nucleosome substrate. We propose to determine X-ray crystal structures of histone modification enzymes associated with human diseases in complex with the nucleosome, using established and novel approaches to crystallize these complicated, multicomponent protein/DNA complexes. We will complement our crystallographic efforts with use of cryoelectron microscopy for three-dimensional structure determination of chromatin enzyme/nucleosome complexes. We also plan to use cryoelectron microscopy to tackle structure determination of native, megadalton sized histone modification enzyme complexes.

项目摘要/摘要 现在，将组蛋白的翻译后修饰作为重要机制建立 调节真核细胞中的基因表达。但是，对如何的结构和机械理解 缺乏组蛋白修饰酶在其核小体底物上的功能。这个缺点限制 可用的遗传，基因组和生化数据的解释，并阻碍 针对与包括癌症在内的人类疾病相关的许多染色质酶的新疗法。 我们专注于通过结构确定组蛋白修饰来解决这些缺陷 与其生理核小体底物结合的酶。我们建议确定X射线晶体结构 与核小体复合物相关的组蛋白修饰酶，使用 建立的新方法可以结晶这些复杂的多组分蛋白/DNA复合物。 我们将使用冷冻电子显微镜进行三维的晶体学工作 染色质酶/核小体复合物的结构测定。我们还计划使用冷冻电子 显微镜以应对天然，梅加达尔顿大小的组蛋白修饰酶的结构测定酶 复合物。