Structural and Functional Analysis of JMJD2D Reveals Molecular Basis for Site-Specific Demethylation among JMJD2 Demethylases
Structural and Functional Analysis of JMJD2D Reveals Molecular Basis for Site-Specific Demethylation among JMJD2 Demethylases
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DOI：
10.1016/j.str.2012.10.018
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发表时间：
2013-01-08
期刊：
影响因子：
5.7
通讯作者：
Trievel, Raymond C.
中科院分区：
文献类型：
--
作者：
Krishnan, Swathi;Trievel, Raymond C.
JMJD2 赖氨酸脱甲基酶 (KDM) 参与多种基因组过程。大多数 JMJD2 同系物对 H3K9me3 和 H3K36me3 表现出双重选择性，但 JMJD2D 除外，它对 H3K9me3 具有特异性。在这里，我们报道了 JMJD2D 中心点 2-氧化戊二酸中心点 H3K9me3 三元复合物和 JMJD2D 脱辅基酶的晶体结构。利用 JMJD2A 的结构比对、分子对接以及一系列组蛋白肽底物的动力学分析，我们阐明了允许 JMJD2A 和 JMJD2D 有效识别 H3K9me3 的特定特征，以及 JMJD2D 中阻碍 H3K36me3 去甲基化的残基。令人惊讶的是，这些结果表明，尽管底物结合构象总体相似，但 JMJD2A 和 JMJD2D 在 H3K9me3 识别方面表现出微妙但重要的差异。此外，我们还发现 H3T11 磷酸化消除了 JMJD2 KDM 的去甲基化作用。总之，这些研究揭示了 JMJD2 位点特异性的分子基础，并为与疾病相关的 JMJD2 KDM 选择性抑制剂的基于结构的设计提供了框架。
JMJD2 lysine demethylases (KDMs) participate in diverse genomic processes. Most JMJD2 homologs display dual selectivity toward H3K9me3 and H3K36me3, with the exception of JMJD2D, which is specific for H3K9me3. Here, we report the crystal structures of the JMJD2D center dot 2-oxoglutarate center dot H3K9me3 ternary complex and JMJD2D apoenzyme. Utilizing structural alignments with JMJD2A, molecular docking, and kinetic analysis with an array of histone peptide substrates, we elucidate the specific signatures that permit efficient recognition of H3K9me3 by JMJD2A and JMJD2D, and the residues in JMJD2D that occlude H3K36me3 demethylation. Surprisingly, these results reveal that JMJD2A and JMJD2D exhibit subtle yet important differences in H3K9me3 recognition, despite the overall similarity in the substrate-binding conformation. Further, we show that H3T11 phosphorylation abrogates demethylation by JMJD2 KDMs. Together, these studies reveal the molecular basis for JMJD2 site specificity and provide a framework for structure-based design of selective inhibitors of JMJD2 KDMs implicated in disease.