Hegedus Zsofia, Grison Claire M, Miles Jennifer A, Rodriguez-Marin Silvia, Warriner Stuart L, Webb Michael E, Wilson Andrew J
School of Chemistry , University of Leeds , Woodhouse Lane , Leeds LS2 9JT , UK . Email:
Astbury Centre For Structural Molecular Biology , University of Leeds , Woodhouse Lane , Leeds LS2 9JT , UK.
Chem Sci. 2019 Feb 21;10(14):3956-3962. doi: 10.1039/c9sc00374f. eCollection 2019 Apr 14.
Foldamers are abiotic molecules that mimic the ability of bio-macromolecules to adopt well-defined and organised secondary, tertiary or quaternary structure. Such templates have enabled the generation of defined architectures which present structurally defined surfaces that can achieve molecular recognition of diverse and complex targets. Far less explored is whether this mimicry of nature can extend to more advanced functions of biological macromolecules such as the generation and activation of catalytic function. In this work, we adopt a novel replacement strategy whereby a segment of protein structure (the S-peptide from RNase S) is replaced by a foldamer that mimics an α-helix. The resultant prosthetic replacement forms a non-covalent complex with the S-protein leading to restoration of catalytic function, despite the absence of a key catalytic residue. Thus this functional protein-proteomimetic complex provides proof that significant segments of protein can be replaced with non-natural building blocks that may, in turn, confer advantageous properties.
折叠体是一类非生物分子，它们能够模拟生物大分子形成明确且有序的二级、三级或四级结构的能力。这类模板能够生成具有特定结构的架构，这些架构呈现出结构明确的表面，从而实现对各种复杂靶标的分子识别。然而，对于这种对自然的模仿是否能够扩展到生物大分子的更高级功能，比如催化功能的产生和激活，人们的探索还很少。在这项工作中，我们采用了一种新颖的替换策略，即将一段蛋白质结构（核糖核酸酶S的S肽段）用一个模拟α螺旋的折叠体进行替换。尽管缺失关键催化残基，但由此产生的假体替换物与S蛋白形成非共价复合物，从而恢复了催化功能。因此，这种功能性蛋白质 - 蛋白质模拟物复合物证明，蛋白质的重要片段可以被非天然构建块所取代，而这些非天然构建块反过来可能赋予有利的特性。
