Coiled-coil formation governed by unnatural hydrophobic core side chains.
Coiled-coil formation governed by unnatural hydrophobic core side chains.
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DOI：
10.1021/ja015912v
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发表时间：
2001-10
影响因子：
15
通讯作者：
N. A. Schnarr;A. J. Kennan
中科院分区：
文献类型：
--
作者：
N. A. Schnarr;A. J. Kennan
蛋白质-蛋白质界面的研究最近引起了广泛的关注。1作为一种普遍存在且易于控制的蛋白质结合方式，R-螺旋卷曲螺旋一直是众多研究的焦点。2.虽然已经收集了大量关于天然核心残基的结构-功能关系的数据，但是侧链候选物的有限数量限制了新型组装体的设计。3在这里，我们报告以非天然疏水侧链的形式引入核心多样性，并证明其在形成特定异源三聚体中的用途。这些结果指向完全非自然界面的发展，这将大大扩展可用的应用范围。卷曲螺旋是由螺旋链（通常为两个或三个）超螺旋形成的非共价聚集体。它们的一级序列包含一个七肽重复序列（abcdefg），在a和d位置具有疏水侧链，其埋藏在紧密堆积的核心中是缔合的主要基础。在作为蛋白质复合介质的作用中，它们执行多种天然功能，从结构支持（R-角蛋白、肌动蛋白等），DNA结合（bZIP转录因子）、受体寡聚化（甘露糖结合蛋白）和膜融合（HIV、流感）。4利用其特异性结合能力的合成类似物已被用于改善蛋白质纯化，指导活性蛋白质复合物的组装，设计亲和传感器和开发新材料。这种广泛的适用性强调了最大多样性和设计灵活性的必要性。本系统描述了通过空间匹配实现的异源三聚化（图1）。位于一个核心位置的小侧链与平行同源三聚体的相对链上的相同残基堆积。由此产生的口袋应该是
The study of protein-protein interfaces has garnered much recent attention. 1 As a ubiquitous and tractable means of governing protein association, the R-helical coiled-coil has been the focus of numerous investigations. 2 Although considerable data have been gathered on the structure-function relationships of natural core residues, the limited number of side chain candidates restricts the design of novel assemblies. 3 Here we report introduction of core diversity in the form of an unnatural hydrophobic side chain, and demonstrate its use in the formation of a specific heterotrimer. These results point toward the development of completely unnatural interfaces that will greatly expand the scope of available applications.Coiled-coils are noncovalent aggregates formed by the supercoiling of helical strands (typically two or three). Their primary sequence contains a heptad repeat (abcdefg) with hydrophobic side chains in a and d positions whose burial in a tightly packed core is the primary basis for association. In their role as mediators of protein complexation they perform manifold natural functions ranging from structural support (R-keratin, actin, etc.) to DNA binding (bZIP transcription factors), receptor oligomerization (mannose binding protein), and membrane fusion (HIV, influenza). 4 Synthetic analogues that exploit their capacity for specific association have been used to improve protein purification, direct the assembly of active protein complexes, design affinity sensors, and develop novel materials. 5 Such broad applicability emphasizes the need for maximal diversity and design flexibility. The present system describes heterotrimerization, achieved through steric matching (Figure 1). A small side chain positioned at one core position packs against the same residue on opposing strands of a parallel homotrimer. The resulting pocket should be