埃默里大學(xué)醫(yī)學(xué)院的研究人員最近確定了與組蛋白修飾有關(guān)的兩種酶的結(jié)構(gòu),。其研究結(jié)果發(fā)表在本周的Nature Structural and Molecular Biology雜志網(wǎng)絡(luò)版上。
這項(xiàng)由Xiaodong Cheng主持的課題組利用X-射線獲得了PHF8和KIAA1718的結(jié)構(gòu),，這兩種酶是兩種重要的組蛋白去甲基化酶(histone demethylases),，能夠消除組蛋白上的甲基化群。如果編碼PHF8酶的基因發(fā)生突變,，將導(dǎo)致一種遺傳性智力低下,。了解酶PHF8的作用機(jī)制將有助于醫(yī)生更好的預(yù)防智力低下。
許多科學(xué)家認(rèn)為組蛋白修飾與“組蛋白密碼”有關(guān),。根據(jù)組蛋白的結(jié)構(gòu)的不同,，細(xì)胞核內(nèi)的DNA相應(yīng)受到限制或保持相對(duì)自由。
據(jù)研究人員Paula Flicker介紹,，這項(xiàng)研究解釋了去甲基化酶處理多個(gè)信號(hào)的分子基礎(chǔ),。為了理解組蛋白去甲基化酶在細(xì)胞內(nèi)的作用,，研究人員將細(xì)胞比作一個(gè)藏書千萬(wàn)的圖書館——為了找到其中的某一本書，你需要了解這些書籍在圖書館中的排布方式,，同樣,，如果想要閱讀DNA信息，也需要一些能夠引導(dǎo)到DNA合適位置的指示,。
組蛋白和纏繞于組蛋白的DNA共同組成核小體，并且每個(gè)組蛋白都有進(jìn)化上保守的N端拖尾伸出核小體之外,，拖尾上可以進(jìn)行一系列包括甲基化在內(nèi)的修飾,。組蛋白上甲基化群的位置不同，其功能也不同,。（生物谷Bioon.com）
生物谷推薦原始出處：
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.
