药学学报, 2021, 56(11): 3014-3029
引用本文:
周理炜, 樊甜甜, 刘同超, 吴小余, 熊兵. 蛋白甲基化识别结构域抑制剂的研究进展[J]. 药学学报, 2021, 56(11): 3014-3029.
ZHOU Li-wei, FAN Tian-tian, LIU Tong-chao, WU Xiao-yu, XIONG Bing. Research progress of protein methylation reader domain inhibitors[J]. Acta Pharmaceutica Sinica, 2021, 56(11): 3014-3029.

蛋白甲基化识别结构域抑制剂的研究进展
周理炜1, 樊甜甜2, 刘同超2, 吴小余1*, 熊兵2*
1. 上海大学理学院化学系, 超分子化学与催化中心, 上海 200444;
2. 中国科学院大学, 中国科学院上海药物研究所, 上海 201203
摘要:
随着质谱和蛋白组学技术的发展,人们对蛋白质翻译后甲基化修饰的研究也取得了长足进步,发现和鉴定了一大批甲基化识别相关蛋白。蛋白翻译后修饰中的甲基化主要发生于赖氨酸和精氨酸,其中赖氨酸可形成单甲基化、双甲基化和三甲基化,而精氨酸则可形成单甲基化、对称或不对称双甲基化。甲基化识别结构域可精确识别不同甲基化程度的赖氨酸或精氨酸,传递甲基化信号,调控下游多种细胞过程,包括基因表达调控、RNA剪接翻译、细胞周期调控等。随着研究的深入,人们发现这些识别蛋白的异常与肿瘤发生发展也密切相关,因而这些甲基化识别蛋白已成为小分子干预的潜在药物靶点。鉴于该领域发展迅猛,本文对多种蛋白甲基化识别结构域进行综述,简介各结构域中重要蛋白及其抑制剂的研究进展,希望能为后续的药物研发提供靶点选择和抑制剂设计的参考。
关键词:    甲基化      甲基化识别结构域      抑制剂      表观遗传学     
Research progress of protein methylation reader domain inhibitors
ZHOU Li-wei1, FAN Tian-tian2, LIU Tong-chao2, WU Xiao-yu1*, XIONG Bing2*
1. Center for Supramolecular Chemistry and Catalysis and Department of Chemistry, College of Sciences, Shanghai University, Shanghai 200444, China;
2. University of Chinese Academy of Sciences, Chinese Academy of Sciences Shanghai Institute of Materia Medica, Shanghai 201203, China
Abstract:
The development of mass spectrometry and proteomics significantly advanced our understanding of post-translational methylation of proteins. In recent years, a large number of proteins containing the methylation recognition domain have been identified. Protein methylation mainly occurs on lysine and arginine residues. Both lysine and arginine have three different methylation states. Lysine can be mono-methylated, di-methylated, and tri-methylated, while the arginine residue can be modified as mono-methylation, symmetrical di-methylation, and asymmetrical di-methylation. Methylation recognition domains can accurately identify lysine or arginine with different state of methylation, transfer methylation signals, and perform functions in a variety of cellular processes, including gene expression regulation, RNA splicing and translation, cell cycle regulation, etc. In recent years, researchers have found that the abnormalities of these recognition proteins are also closely related to the genesis and development of tumors. Therefore, these methylation recognition proteins were considered as potential drug targets for small molecule intervention. In this review, we summarized the researches on the recognition domains of protein methylation as well as their inhibitors, hoping to provide the basis for further drug development in this field.
Key words:    methylation    methylation recognition domain    inhibitor    epigenetics   
收稿日期: 2021-04-06
DOI: 10.16438/j.0513-4870.2021-0486
基金项目: 国家“新药创制”科技重大专项基金项目(2018ZX09711002-004);自然科学基金面上资助项目(81773572).
通讯作者: 吴小余,Tel:13661970096,E-mail:bxiong@simm.ac.cn;熊兵,E-mail:wuxy@shu.edu.cn
Email: bxiong@simm.ac.cn;wuxy@shu.edu.cn
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