Heterogeneous-Backbone Foldamer Mimics of Zinc Finger Tertiary Structure.
Heterogeneous-Backbone Foldamer Mimics of Zinc Finger Tertiary Structure.
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锌指三级结构的异源骨架折叠体模拟物。
DOI：
10.1021/jacs.7b03114
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发表时间：
2017-06-14
影响因子：
15
通讯作者：
Horne WS
中科院分区：
文献类型：
--
作者：
George KL;Horne WS
具有偏离生物大分子的组成的多种寡聚主链可以以限定的方式折叠。被称为“折叠体”的这些试剂具有不同的潜在应用。许多蛋白质启发的二级结构（例如，螺旋、片层）已经由非天然骨架产生，然而三级折叠在单个实体中结合几个二级结构元件的例子是罕见的。解决这一挑战的一个有希望的策略是天然蛋白质序列的系统性主链改变，通过该改变，侧链的子集被展示在非天然构建块上以产生异质性主链。这种方法的缺点是在多于一个或两个位点处的取代通常以折叠稳定性的显著能量成本来实现。在这里，我们报告的异质骨干折叠体，模仿锌指结构域，一个普遍存在的和生物学上重要的金属结合的第三基序，这样做的折叠稳定性是上级的天然蛋白质，他们的设计是基于。紫外-可见光谱、等温滴定量热法和多维NMR的组合揭示，具有>20%修饰的主链的适当设计的寡聚物可以形成天然样三级折叠，其具有与原型序列相同的金属结合环境（特异性因子1的第三指）和增强的热力学稳定性。这些结果将异质性骨架折叠体设计的范围扩展到新的三级结构类别，并表明明智地应用骨架修饰可以伴随着折叠稳定性的改善。
A variety of oligomeric backbones with compositions deviating from biomacromolecules can fold in defined ways. Termed “foldamers,” these agents have diverse potential applications. A number of protein-inspired secondary structures (e.g., helices, sheets) have been produced from unnatural backbones, yet examples of tertiary folds combining several secondary structural elements in a single entity are rare. One promising strategy to address this challenge is the systematic backbone alteration of natural protein sequences, through which a subset of the side chains is displayed on an unnatural building block to generate a heterogeneous backbone. A drawback to this approach is that substitution at more than one or two sites often comes at a significant energetic cost to fold stability. Here we report heterogeneous-backbone foldamers that mimic the zinc finger domain, a ubiquitous and biologically important metal-binding tertiary motif, and do so with a folded stability that is superior to the natural protein on which their design is based. A combination of UV-vis spectroscopy, isothermal titration calorimetry, and multidimensional NMR reveals that suitably designed oligomers with >20% modified backbones can form native-like tertiary folds with metal-binding environments identical to the prototype sequence (the third finger of specificity factor 1) and enhanced thermodynamic stability. These results expand the scope of heterogeneous-backbone foldamer design to a new tertiary structure class and show that judiciously applied backbone modification can be accompanied by improvement to fold stability.
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