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首页> 外文期刊>Acta crystallographica.Section D. Biological crystallography >Structures of histone methyltransferase SET7/9 in complexes with adenosylmethionine derivatives
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Structures of histone methyltransferase SET7/9 in complexes with adenosylmethionine derivatives

机译：组蛋白甲基转移酶结构SET7/9配合物与腺苷甲硫氨酸衍生品

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摘要

SET7/9 is a protein lysine methyltransferase that methylates histone H3 and nonhistone proteins such as p53, TAF10 and oestrogen receptor . In previous work, novel inhibitors of SET7/9 that are amine analogues of the coenzyme S-(5′-adenosyl)-l-methionine (AdoMet) have been developed. Here, crystal structures of SET7/9 are reported in complexes with two AdoMet analogues, designated DAAM-3 and AAM-1, in which an n-hexylaminoethyl group or an n-hexyl group is attached to the N atom that replaces the S atom of AdoMet, respectively. In both structures, the inhibitors bind to the coenzyme-binding site and their additional alkyl chain binds in the lysine-access channel. The N atom in the azaalkyl chain of DAAM-3 is located at almost the same position as the N-methyl C atom of the methylated lysine side chain in the substrate-peptide complex structures and stabilizes complex formation by hydrogen bonding to the substrate-binding site residues of SET7/9. On the other hand, the alkyl chain of AAM-1, which is a weaker inhibitor than DAAM-3, binds in the lysine-access channel only through hydrophobic and van der Waals interactions. Unexpectedly, the substrate-binding site of SET7/9 complexed with AAM-1 specifically interacts with the artificial N-terminal sequence of an adjacent symmetry-related molecule, presumably stabilizing the alkyl chain of AAM-1.
机译：SET7/9是一种蛋白质赖氨酸甲基转移酶甲基化组蛋白H3和非组蛋白的蛋白质如p53、TAF10和雌激素受体。以往的研究中,小说的SET7/9抑制剂辅酶的胺类似物吗(S) - 5 ' -adenosyl -l-methionine (AdoMet)发展。在小区有两个AdoMet类似物,一个指定DAAM-3 AAM-1,n-hexylaminoethyl组或n-hexyl组附加到N原子取代了S原子分别为AdoMet。抑制剂结合coenzyme-binding站点他们额外的烷基链的结合lysine-access通道。链DAAM-3位于几乎相同地位N-methyl C原子的甲基化substrate-peptide赖氨酸侧链复杂的结构和稳定复杂通过氢键形成substrate-binding网站SET7/9的残留物。另一方面,AAM-1的烷基链,这是一个较弱的比DAAM-3抑制剂,结合只有通过疏水lysine-access通道和范德瓦耳斯相互作用。substrate-binding SET7/9包裹着AAM-1专门与人工交互氨基端序列相邻symmetry-related分子,大概稳定AAM-1的烷基链。

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