Structural Basis of Substrate Methylation and Inhibition of SMYD2
Structural Basis of Substrate Methylation and Inhibition of SMYD2
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DOI：
10.1016/j.str.2011.06.011
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发表时间：
2011-09-07
期刊：
影响因子：
5.7
通讯作者：
Keen, Nicholas
中科院分区：
文献类型：
--
作者：
Ferguson, Andrew D.;Larsen, Nicholas A.;Keen, Nicholas
蛋白质赖氨酸甲基转移酶是表观遗传信号传导的重要调节因子。这些酶催化供体甲基从S-腺苷甲硫氨酸转移到组蛋白上的特异性受体赖氨酸，导致染色质结构和转录调控的变化。这些酶也甲基化非组蛋白质底物，揭示了调节细胞生理学的额外机制。致癌蛋白SMYD 2抑制肿瘤抑制蛋白p53和Rb的功能活性，使其成为有吸引力的药物靶标。在这里，我们报告了AZ 505的发现，AZ 505是从高通量化学筛选中鉴定的SMYD 2的有效和选择性抑制剂。我们还展示了SMYD 2与p53底物和产物肽的晶体结构，特别是与AZ 505的复合物。这种底物竞争性抑制剂结合在SMYD 2的肽结合沟中。这些结果对SMYD 2抑制剂的开发具有意义，并表明开发针对这类靶点的新型疗法的潜力。
Protein lysine methyltransferases are important regulators of epigenetic signaling. These enzymes catalyze the transfer of donor methyl groups from S-adenosylmethionine to specific acceptor lysines on histones, leading to changes in chromatin structure and transcriptional regulation. These enzymes also methylate nonhistone protein substrates, revealing an additional mechanism to regulate cellular physiology. The oncogenic protein SMYD2 represses the functional activities of the tumor suppressor proteins p53 and Rb, making it an attractive drug target. Here we report the discovery of AZ505, a potent and selective inhibitor of SMYD2 that was identified from a high throughput chemical screen. We also present the crystal structures of SMYD2 with p53 substrate and product peptides, and notably, in complex with AZ505. This substrate competitive inhibitor is bound in the peptide binding groove of SMYD2. These results have implications for the development of SMYD2 inhibitors, and indicate the potential for developing novel therapies targeting this target class.