Histone Lysine Methylation: Structures and Functions

组蛋白赖氨酸甲基化：结构和功能

• 批准号: 7071250
• 负责人: Xiaodong Cheng
• 金额: $ 26.78万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7071250
• 关键词: Arabidopsis; Neurospora; SDS polyacrylamide gel electrophoresis; carcinogenesis; enzyme activity; enzyme inhibitors; enzyme structure; enzyme substrate; gene expression; histones; human tissue; lysine; mass spectrometry; methylation; methyltransferase; protein structure function; site directed mutagenesis

DESCRIPTION (provided by applicant): Histone lysine methylation is part of the "histone code" that can profoundly influence chromatin function. The overall goal of this project is to understand the substrate and product specificites of histone lysine methyltrasferases (HKMTs) by determining their structures alone and in complex with various substrate histone peptides. Specifically, we propose (1) to investigate the structural basis for substrate specificity (histone tail recognition) and product specificity (mono-, di- or tri-methylation of lysine) of a number of HKMTs; (2) to investigate the biochemical properties of HKMTs and their variants; and (3) to investigate the structural and biochemical properties of several nucleosome-dependent HKMTs. Understanding the structural basis for the product specificity of HKMTs is a central aim of this proposal. Mutations of human HKMTs are frequently associated with diseases including cancer. Because chromatin structure affects gene expression, HMKTs are emerging as major players in the regulation of gene expression and, when deregulated, as inducers of cancer. One of the ultimate goals for the structural and biochemical analysis of HKMTs is to find inhibitors that may be of pharmaceutical value.

描述（由申请人提供）：组蛋白赖氨酸甲基化是“组蛋白密码”的一部分，可以深刻影响染色质功能。该项目的总体目标是通过确定组蛋白赖氨酸甲基转移酶 (HKMT) 的单独结构以及与各种底物组蛋白肽的复合物的结构来了解组蛋白赖氨酸甲基转移酶 (HKMT) 的底物和产物特异性。具体来说，我们建议（1）研究一些HKMT的底物特异性（组蛋白尾部识别）和产物特异性（赖氨酸的单甲基化、二甲基化或三甲基化）的结构基础； (2) 研究HKMTs及其变异体的生化特性； (3) 研究几种核小体依赖性 HKMT 的结构和生化特性。了解 HKMT 产品特殊性的结构基础是本提案的核心目标。人类 HKMT 突变通常与包括癌症在内的疾病相关。由于染色质结构影响基因表达，HMKT 正在成为基因表达调节的主要参与者，并且当解除调节时，可作为癌症的诱导剂。 HKMT结构和生化分析的最终目标之一是寻找可能具有药用价值的抑制剂。