DNMT1 激活的结构基础。
Structural basis for activation of DNMT1.
机构信息
Structural Biology Laboratory, Graduate School of Medical Life Science, Yokohama City University, Tsurumi-ku, Yokohama, Kanagawa, 230-0045, Japan.
Synchrotron Radiation Research Center, Nagoya University, Furo-Cho, Chikusa-Ku, Nagoya, 464-8603, Japan.
出版信息
Nat Commun. 2022 Nov 21;13(1):7130. doi: 10.1038/s41467-022-34779-4.
DNMT1 is an essential enzyme that maintains genomic DNA methylation, and its function is regulated by mechanisms that are not yet fully understood. Here, we report the cryo-EM structure of human DNMT1 bound to its two natural activators: hemimethylated DNA and ubiquitinated histone H3. We find that a hitherto unstudied linker, between the RFTS and CXXC domains, plays a key role for activation. It contains a conserved α-helix which engages a crucial "Toggle" pocket, displacing a previously described inhibitory linker, and allowing the DNA Recognition Helix to spring into the active conformation. This is accompanied by large-scale reorganization of the inhibitory RFTS and CXXC domains, allowing the enzyme to gain full activity. Our results therefore provide a mechanistic basis for the activation of DNMT1, with consequences for basic research and drug design.
DNMT1 是一种维持基因组 DNA 甲基化的必需酶，其功能受到尚未完全了解的机制的调节。在这里，我们报告了与人 DNMT1 结合的两种天然激活剂：半甲基化 DNA 和泛素化组蛋白 H3 的冷冻电镜结构。我们发现，在 RFTS 和 CXXC 结构域之间的一个迄今为止尚未研究的连接子对于激活起着关键作用。它包含一个保守的α-螺旋，与一个关键的“Toggle”口袋结合，取代了先前描述的抑制性连接子，并允许 DNA 识别螺旋进入活性构象。这伴随着抑制性 RFTS 和 CXXC 结构域的大规模重组，使酶获得完全的活性。因此，我们的结果为 DNMT1 的激活提供了一个机制基础，对基础研究和药物设计具有重要意义。
Zotero 插件