Sequence Specificity in the Entropy-Driven Binding of a Small Molecule and a Disordered Peptide
Sequence Specificity in the Entropy-Driven Binding of a Small Molecule and a Disordered Peptide
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DOI：
10.1016/j.jmb.2017.07.016
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发表时间：
2017-09-01
影响因子：
5.6
通讯作者：
Vendruscolo, Michele
中科院分区：
文献类型：
--
作者：
Heller, Gabriella T.;Aprilel, Francesco A.;Vendruscolo, Michele
大约三分之一的人类蛋白质组由完全无序或包含扩展无序区域的蛋白质组成。尽管这些无序蛋白与许多重大疾病密切相关，但它们与小分子的结合机制仍然知之甚少，主要问题是它们的特异性是否足以用于药物开发。在这里，通过研究小分子和来自癌基因蛋白 c-Myc 的无序肽的相互作用，我们描述了一种“特异性-扩散”结合机制，尽管具有熵性质，但仍表现出序列特异性。通过结合核磁共振波谱、生物物理测量、统计推断和分子模拟，我们提供了这种序列特异性的定量测量，并将其与尿素相互作用的情况进行比较，尿素相互作用是分散的但不具体。为了研究这种类型的结合是否通常可以改变分子间相互作用，我们证明它会导致肽聚集的抑制。这些结果表明，我们报告的结合机制可能会创造新的机会来发现以特定方式靶向单体状态的无序蛋白质的药物。 (C) 2017 年作者。由爱思唯尔有限公司出版
Approximately one-third of the human proteome is made up of proteins that are entirely disordered or that contain extended disordered regions. Although these disordered proteins are closely linked with many major diseases, their binding mechanisms with small molecules remain poorly understood, and a major concern is whether their specificity can be sufficient for drug development. Here, by studying the interaction of a small molecule and a disordered peptide from the oncogene protein c-Myc, we describe a "specific-diffuse" binding mechanism that exhibits sequence specificity despite being of entropic nature. By combining NMR spectroscopy, biophysical measurements, statistical inference, and molecular simulations, we provide a quantitative measure of such sequence specificity and compare it to the case of the interaction of urea, which is diffuse but not specific. To investigate whether this type of binding can generally modify intermolecular interactions, we show that it leads to an inhibition of the aggregation of the peptide. These results suggest that the binding mechanism that we report may create novel opportunities to discover drugs that target disordered proteins in their monomeric states in a specific manner. (C) 2017 The Authors. Published by Elsevier Ltd.