McGovern Róise E, Snarr Brendan D, Lyons Joseph A, McFarlane James, Whiting Amanda L, Paci Irina, Hof Fraser, Crowley Peter B
School of Chemistry, National University of Ireland Galway, University Road, Galway, Ireland.
Department of Chemistry, University of Victoria, British Columbia, V8W 3V6, Canada.
Chem Sci. 2015 Jan 1;6(1):442-449. doi: 10.1039/C4SC02383H.
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 -sulfonatocalix[4]arene (sclx) bound to methylated lysozyme in which the lysine residues were chemically modified from Lys-NH to Lys-NH(Me). Of the six possible dimethyllysine sites, sclx selected Lys116-Me and the dimethylamino substituent was deeply buried in the calixarene cavity. This complex confirms the tendency for Lys-Me 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-Me in solution. The structure presented here may serve as a stepping stone to the development of new biochemical reagents that target methylated lysines.
赖氨酸是蛋白质表面普遍存在的残基。赖氨酸的翻译后修饰，包括甲基化形成单甲基、二甲基或三甲基胺，会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修饰此类通路的潜在工具。为了在这个方向取得进展，需要与甲基化赖氨酸形成复合物的配体的详细结构数据。在此，我们报道了一种与甲基化溶菌酶结合的磺化杯[4]芳烃（sclx）的晶体结构，其中赖氨酸残基从Lys-NH化学修饰为Lys-NH(Me)。在六个可能的二甲基赖氨酸位点中，sclx选择了Lys116-Me，二甲基氨基取代基深埋在杯芳烃腔内。该复合物证实了Lys-Me残基形成阳离子-π相互作用的倾向，这已被证明在蛋白质识别带有甲基化赖氨酸的组蛋白尾巴中很重要。来自核磁共振光谱和分子动力学模拟的支持数据证实了溶液中对Lys116-Me的选择性。此处呈现的结构可能是开发靶向甲基化赖氨酸的新型生化试剂的垫脚石。
