Structural study of a small molecule receptor bound to dimethyllysine in lysozyme.
Structural study of a small molecule receptor bound to dimethyllysine in lysozyme.
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DOI：
10.1039/c4sc02383h
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发表时间：
2015-01-01
期刊：
影响因子：
8.4
通讯作者：
Crowley PB
中科院分区：
文献类型：
--
作者：
McGovern RE;Snarr BD;Lyons JA;McFarlane J;Whiting AL;Paci I;Hof F;Crowley PB
x射线晶体学揭示了杯芳烃如何与二甲基赖氨酸结合，形成与组蛋白尾部结合的色域芳香笼基序相似的复合物。赖氨酸是蛋白质表面普遍存在的残留物。赖氨酸的翻译后修饰，包括甲基化为单、二或三甲基化胺，导致化学和结构改变，对蛋白质相互作用和信号通路产生重大影响。与甲基化赖氨酸结合的小分子是改变这种途径的潜在工具。为了在这方面取得进展，需要甲基化赖氨酸络合物配体的详细结构数据。在这里，我们报道了一个结合甲基化溶菌酶的对磺酰基[4]芳烃（sclx4）的晶体结构，其中赖氨酸残基从Lys-NH3 +化学修饰为Lys-NH(Me2)+。在6个可能的二甲基赖氨酸位点中，sclx4选择了Lys116-Me2，二甲胺取代基深埋在杯芳烃腔中。这个复合物证实了赖氨酸- me2残基形成阳离子-π相互作用的趋势，这在含有甲基化赖氨酸的组蛋白尾部的蛋白质识别中是重要的。核磁共振波谱和MD模拟的支持数据证实了溶液中Lys116-Me2的选择性。本文提出的结构可以作为开发针对甲基化赖氨酸的新生化试剂的垫脚石。
X-ray crystallography reveals how a calixarene can bind to dimethyllysine to form a complex with features similar to the aromatic cage motif of a chromodomain bound to a histone tail. Lysine is a ubiquitous residue on protein surfaces. Post translational modifications of lysine, including methylation to the mono-, di- or trimethylated amine result in chemical and structural alterations that have major consequences for protein interactions and signalling pathways. Small molecules that bind to methylated lysines are potential tools to modify such pathways. To make progress in this direction, detailed structural data of ligands in complex with methylated lysine is required. Here, we report a crystal structure of p-sulfonatocalix[4]arene (sclx4) bound to methylated lysozyme in which the lysine residues were chemically modified from Lys-NH3 + to Lys-NH(Me2)+. Of the six possible dimethyllysine sites, sclx4 selected Lys116-Me2 and the dimethylamino substituent was deeply buried in the calixarene cavity. This complex confirms the tendency for Lys-Me2 residues to form cation–π interactions, which have been shown to be important in protein recognition of histone tails bearing methylated lysines. Supporting data from NMR spectroscopy and MD simulations confirm the selectivity for Lys116-Me2 in solution. The structure presented here may serve as a stepping stone to the development of new biochemical reagents that target methylated lysines.