Molecular basis for oncohistone H3 recognition by SETD2 methyltransferase.
Molecular basis for oncohistone H3 recognition by SETD2 methyltransferase.
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DOI：
10.1101/gad.284323.116
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发表时间：
2016-07-15
影响因子：
10.5
通讯作者：
Li H
中科院分区：
文献类型：
--
作者：
Yang S;Zheng X;Lu C;Li GM;Allis CD;Li H
Yang等人报道了与具有SAH的H3 K36 M或H3 K36 I肽结合的SETD 2催化结构域的晶体结构。在复合物结构中，催化SET结构域采用开放构象，K36 M/I肽紧密地定位在新形成的底物通道中。编码组蛋白的基因的高频点突变最近已被确定为许多肿瘤中的新驱动因素。具体而言，H3 K36 M/I突变在成软骨细胞瘤和未分化肉瘤中通过抑制H3 K36甲基转移酶（包括SETD 2）而显示出致癌性。在这里，我们报告的晶体结构的SETD 2催化结构域结合到H3 K36 M或H3 K36 I肽与SAH（S-腺苷高半胱氨酸）。在复合物结构中，催化结构域采用开放构象，K36 M/I肽紧密地定位在新形成的底物通道中。我们的结构和生化数据揭示了致癌组蛋白识别和抑制SETD 2的分子基础。
Yang et al. report the crystal structures of the SETD2 catalytic domain bound to H3K36M or H3K36I peptides with SAH. In the complex structure, the catalytic SET domain adopts an open conformation, with the K36M/I peptide snuggly positioned in a newly formed substrate channel. High-frequency point mutations of genes encoding histones have been identified recently as novel drivers in a number of tumors. Specifically, the H3K36M/I mutations were shown to be oncogenic in chondroblastomas and undifferentiated sarcomas by inhibiting H3K36 methyltransferases, including SETD2. Here we report the crystal structures of the SETD2 catalytic domain bound to H3K36M or H3K36I peptides with SAH (S-adenosylhomocysteine). In the complex structure, the catalytic domain adopts an open conformation, with the K36M/I peptide snuggly positioned in a newly formed substrate channel. Our structural and biochemical data reveal the molecular basis underying oncohistone recognition by and inhibition of SETD2.