埃默里大学医学院的研究人员最近确定了与组蛋白修饰有关的两种酶的结构。其研究结果发表在本周的Nature Structural and Molecular Biology杂志网络版上。
这项由Xiaodong Cheng主持的课题组利用X-射线获得了PHF8和KIAA1718的结构，这两种酶是两种重要的组蛋白去甲基化酶(histone demethylases)，能够消除组蛋白上的甲基化群。如果编码PHF8酶的基因发生突变，将导致一种遗传性智力低下。了解酶PHF8的作用机制将有助于医生更好的预防智力低下。
许多科学家认为组蛋白修饰与“组蛋白密码”有关。根据组蛋白的结构的不同，细胞核内的DNA相应受到限制或保持相对自由。
据研究人员Paula Flicker介绍，这项研究解释了去甲基化酶处理多个信号的分子基础。为了理解组蛋白去甲基化酶在细胞内的作用，研究人员将细胞比作一个藏书千万的图书馆——为了找到其中的某一本书，你需要了解这些书籍在图书馆中的排布方式，同样，如果想要阅读DNA信息，也需要一些能够引导到DNA合适位置的指示。
组蛋白和缠绕于组蛋白的DNA共同组成核小体，并且每个组蛋白都有进化上保守的N端拖尾伸出核小体之外，拖尾上可以进行一系列包括甲基化在内的修饰。组蛋白上甲基化群的位置不同，其功能也不同。（中国酶制剂www.cnenzyme.com ）
生物谷推荐原始出处：
Nature Structural & Molecular Biology 16, 312 - 317 (2009) 15 February 2009 | doi:10.1038/nsmb.1560
Structural basis for G9a-like protein lysine methyltransferase inhibition by BIX-01294
Yanqi Chang1, Xing Zhang1, John R Horton1, Anup K Upadhyay1, Astrid Spannhoff2, Jin Liu3, James P Snyder3, Mark T Bedford2 & Xiaodong Cheng1
Histone lysine methylation is an important epigenetic mark that regulates gene expression and chromatin organization. G9a and G9a-like protein (GLP) are euchromatin-associated methyltransferases that repress transcription by methylating histone H3 Lys9. BIX-01294 was originally identified as a G9a inhibitor during a chemical library screen of small molecules and has previously been used in the generation of induced pluripotent stem cells. Here we present the crystal structure of the catalytic SET domain of GLP in complex with BIX-01294 and S-adenosyl-L-homocysteine. The inhibitor is bound in the substrate peptide groove at the location where the histone H3 residues N-terminal to the target lysine lie in the previously solved structure of the complex with histone peptide. The inhibitor resembles the bound conformation of histone H3 Lys4 to Arg8, and is positioned in place by residues specific for G9a and GLP through specific interactions.
1 Department of Biochemistry, Emory University School of Medicine, 1510 Clifton Road, Atlanta, Georgia 30322, USA.
2 M.D. Anderson Cancer Center, Department of Carcinogenesis, University of Texas, 1808 Park Road 1C, Smithville, Texas 78957, USA.
3 Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, Georgia 30322, USA.
