Histone Lysine Methylation: Structures and Functions

描述(申请人提供)：组蛋白赖氨酸甲基化是“组蛋白密码”的一部分，可深刻影响染色质功能。该项目的总体目标是通过单独确定组蛋白赖氨酸甲基转移酶(HKMTs)的结构以及与各种底物组蛋白多肽的复合体来了解组蛋白赖氨酸甲基转移酶(HKMTs)的底物和产物的特异性。具体地说，我们建议(1)研究一些HKMT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HKMT及其变异体的生化性质；(3)研究几种依赖核小体的HKMT的结构和生化性质。理解HKMT产品专用性的结构基础是这项建议的主要目的。人类HKMT的突变经常与包括癌症在内的疾病有关。由于染色质结构影响基因表达，HMKT正在成为基因表达调控的主要参与者，当基因表达被解除调控时，HMKT成为癌症的诱导者。HKMT的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。

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.