Mechanism of histone lysine methyl transfer revealed by the structure of SET7/9-AdoMet
Mechanism of histone lysine methyl transfer revealed by the structure of SET7/9-AdoMet
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DOI：
10.1093/emboj/cdg025
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发表时间：
2003-01-15
期刊：
影响因子：
11.4
通讯作者：
Cho, YJ
中科院分区：
文献类型：
--
作者：
Kwon, T;Chang, JH;Cho, YJ
组蛋白赖氨酸残基的甲基化在染色质结构和基因表达调控中起着关键作用。在这里，我们报告了两个晶体结构的SET 7/9，组蛋白甲基转移酶（HMTase），转移甲基组蛋白H3的赖氨酸4，在复杂的S-腺苷-L-甲硫氨酸（蛋氨酸）确定在1.7和2.3埃分辨率。这些结构揭示了由以下组成的活性位点：（i）SET结构域和c-SET螺旋之间的结合口袋，其中处于不寻常构象的c-SET分子结合;（ii）仅未甲基化的赖氨酸残基可以进入的狭窄底物特异性通道;和（iii）催化酪氨酸残基。甲硫氨酸的甲基被引导至狭窄通道，其中底物赖氨酸从相对侧进入。我们证明，SET 7/9可以转移两个，但不是三个甲基未经修饰的赖氨酸4的H3没有底物解离。SET结构域的HMTase的不寻常的功能区分未甲基化和甲基化的赖氨酸底物，和组蛋白H3尾部的甲基化位点。
The methylation of lysine residues of histones plays a pivotal role in the regulation of chromatin structure and gene expression. Here, we report two crystal structures of SET7/9, a histone methyltransferase (HMTase) that transfers methyl groups to Lys4 of histone H3, in complex with S-adenosyl-L-methionine (AdoMet) determined at 1.7 and 2.3 Angstrom resolution. The structures reveal an active site consisting of: (i) a binding pocket between the SET domain and a c-SET helix where an AdoMet molecule in an unusual conformation binds; (ii) a narrow substrate-specific channel that only unmethylated lysine residues can access; and (iii) a catalytic tyrosine residue. The methyl group of AdoMet is directed to the narrow channel where a substrate lysine enters from the opposite side. We demonstrate that SET7/9 can transfer two but not three methyl groups to unmodified Lys4 of H3 without substrate dissociation. The unusual features of the SET domain-containing HMTase discriminate between the un- and methylated lysine substrate, and the methylation sites for the histone H3 tail.