Design of a Short Thermally Stable α-Helix Embedded in a Macrocycle.
Design of a Short Thermally Stable α-Helix Embedded in a Macrocycle.
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嵌入大环中的短热稳定α-螺旋的设计。
DOI：
10.1002/cbic.201800026
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发表时间：
2018-05-04
期刊：
影响因子：
--
通讯作者：
DeGrado WF
中科院分区：
文献类型：
--
作者：
Wu H;Acharyya A;Wu Y;Liu L;Jo H;Gai F;DeGrado WF
虽然螺旋在肽-蛋白和蛋白-蛋白相互作用中起着关键作用，但在没有结合伙伴的水溶液中，短肽（10-15个残基）的螺旋构象通常是不稳定的。因此，稳定肽的螺旋构象可以增加结合效力、特异性和蛋白水解降解的稳定性。通过在螺旋的中心部分引入侧链对侧链交联，螺旋已经成功地稳定了。然而，这种方法使螺旋的末端游离，从而导致非氢键酰胺基团的磨损和暴露在溶剂中。在这里，我们开发了一种“带帽”肽策略，通过将螺旋的整个长度嵌入一个大周期内来稳定螺旋，该大周期还包括半刚性有机模板以及端盖相互作用。我们设计了一个带有十个残基的螺旋肽，它的行为就像一个微型蛋白，具有协同热展开转变和Tm≈70°C，这对于这种长度的螺旋肽来说是前所未有的。核磁共振结构测定证实了该设计，x射线晶体学揭示了一种新的四元结构，对文件夹设计具有指导意义。
Although helices play key roles in peptide–protein and protein–protein interactions, the helical conformation is generally unstable for short peptides (10–15 residues) in aqueous solution in the absence of their binding partners. Thus, stabilizing the helical conformation of peptides can lead to increases in binding potency, specificity, and stability towards proteolytic degradation. Helices have been successfully stabilized by introducing side chain-to-side chain crosslinks within the central portion of the helix. However, this approach leaves the ends of the helix free, thus leading to fraying and exposure of the non-hydrogen-bonded amide groups to solvent. Here, we develop a “capped-strapped” peptide strategy to stabilize helices by embedding the entire length of the helix within a macrocycle, which also includes a semirigid organic template as well as end-capping interactions. We have designed a ten-residue capped-strapped helical peptide that behaves like a miniprotein, with a cooperative thermal unfolding transition and Tm ≈70°C, unprecedented for helical peptides of this length. The NMR structure determination confirmed the design, and X-ray crystallography revealed a novel quaternary structure with implications for foldamer design.
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影响因子：
64.8
作者：
Bhardwaj, Gaurav;Mulligan, Vikram Khipple;Bahl, Christopher D.;Gilmore, Jason M.;Harvey, Peta J.;Cheneval, Olivier;Buchko, Garry W.;Pulavarti, Surya V. S. R. K.;Kaas, Quentin;Eletsky, Alexander;Huang, Po-Ssu;Johnsen, William A.;Greisen, Per Jr;Rocklin, Gabriel J.;Song, Yifan;Linsky, Thomas W.;Watkins, Andrew;Rettie, Stephen A.;Xu, Xianzhong;Carter, Lauren P.;Bonneau, Richard;Olson, James M.;Coutsias, Evangelos;Correnti, Colin E.;Szyperski, Thomas;Craik, David J.;Baker, David
通讯作者：
Baker, David
DOI：
10.1073/pnas.0504613102
发表时间：
2005-09-27
影响因子：
11.1
作者：
Clark, RJ;Fischer, H;Craik, DJ
通讯作者：
Craik, DJ
影响因子：
16.6
作者：
Clark, Richard J.;Jensen, Jonas;Craik, David J.
通讯作者：
Craik, David J.
影响因子：
16.6
作者：
Fremaux, Juliette;Mauran, Laura;Guichard, Gilles
通讯作者：
Guichard, Gilles
DOI：
10.1073/pnas.1710695114
发表时间：
2017-10-10
影响因子：
11.1
作者：
Dang, Bobo;Wu, Haifan;DeGrado, William F.
通讯作者：
DeGrado, William F.