Crystal structure of histone demethylase LSD1 and tranylcypromine at 2.25 Å
Crystal structure of histone demethylase LSD1 and tranylcypromine at 2.25 Å
复制标题
DOI：
10.1016/j.bbrc.2007.11.066
复制
发表时间：
2008-02-01
影响因子：
3.1
通讯作者：
Yokoyama, Shigeyuki
中科院分区：
文献类型：
--
作者：
Mimasu, Shinya;Sengoku, Toru;Yokoyama, Shigeyuki
转录活性和染色质结构可及性与特定组蛋白残基的甲基化相关。赖氨酸特异性去甲基化酶1（LSD 1）是第一个发现的组蛋白去甲基化酶，其利用FAD使组蛋白H3的Lys 4或Lys 9去甲基化。在已知的单胺氧化酶抑制剂中，反苯环丙胺（Parnate）对LSD 1显示出最有效的抑制作用。最近，LSD 1和反苯环丙胺的晶体结构在2.75埃下解析，揭示了与LSD 1的黄素稠合的五元环。在这项研究中，我们将LSD 1-反苯环丙胺复合物的晶体结构细化到2.25埃。五元环模型与电子密度并不完全吻合，给出的R-work/R-free值为0.226/0.254。另一方面，N（5）加合物在测试的模型中给出了最低的R-work/R-free值，为0.218/0.248。这些结果表明，LSD 1-反苯环丙胺复合物不是完全由五元加合物组成，而是部分含有中间体，如N（5）加合物。(C)2007爱思唯尔公司All rights reserved.
Transcriptional activity and chromatin structure accessibility are correlated with the methylation of specific histone residues. Lysine-specific demethylase 1 (LSD1) is the first discovered histone demethylase, which demethylates Lys4 or Lys9 of histone H3, using FAD. Among the known monoamine oxidase inhibitors, tranylcypromine (Parnate) showed the most potent inhibitory effect on LSD1. Recently, the crystal structure of LSD1 and tranylcypromine was solved at 2.75 angstrom, revealing a five-membered ring fused to the flavin of LSD1. In this study, we refined the crystal structure of the LSD1-tranylcypromine complex to 2.25 angstrom. The five-membered ring model did not fit completely with the electron density, giving R-work/R-free values of 0.226/0.254. On the other hand, the N(5) adduct gave the lowest R-work/R-free values of 0.218/0.248, among the tested models. These results imply that the LSD1-tranylcypromine complex is not completely composed of the five-membered adduct, but partially contains an intermediate, such as the N(5) adduct. (C) 2007 Elsevier Inc. All rights reserved.