Truncated and helix-constrained peptides with high affinity and specificity for the cFos coiled-coil of AP-1.
Truncated and helix-constrained peptides with high affinity and specificity for the cFos coiled-coil of AP-1.
复制标题
DOI：
10.1371/journal.pone.0059415
复制
发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Mason JM
中科院分区：
文献类型：
--
作者：
Rao T;Ruiz-Gómez G;Hill TA;Hoang HN;Fairlie DP;Mason JM
基于蛋白质的疗法具有大的相互作用表面。蛋白质折叠赋予局部表面表位结构稳定性，在与结合配偶体相互作用时赋予高亲和力和靶特异性。然而，具有对应于此类蛋白质表位的序列的短合成肽在水中是非结构化的，并且以低亲和力和特异性混杂地结合蛋白质。在这里，我们结合联合收割机的结构稳定性和目标特异性的蛋白质，低成本和快速合成的小分子，以满足显着的挑战结合卷曲螺旋蛋白的转录调控。通过迭代地将基于Jun的肽从37个残基截短到22个残基，策略性地引入i→i+4螺旋诱导约束，并定位非天然氨基酸，我们已经产生了结合cFos的短的、水稳定的α-螺旋肽。一种肽的三维NMR衍生结构（24）证实了高度稳定的α-螺旋，其对血清中的蛋白水解降解具有抗性。这些短结构的肽被熵预组织以高亲和力和特异性结合cFos，cFos是致癌转录调节因子激活蛋白-1（AP-1）的关键组分。它们竞争性地拮抗cJun-cFos卷曲螺旋相互作用。将基于Jun的肽从37个残基截短至22个残基使cJun的结合焓降低了1.99 kcal/mol，但这被增加的构象熵（TΔS ≤7.5 kcal/mol）补偿。本研究表明，合理设计α-螺旋环五肽模块约束的短肽能够保留亲本的高螺旋度，以及对cFos的高亲和力和特异性。这些是朝向cJun-cFos相互作用的小拮抗剂的重要步骤，cJun-cFos相互作用介导癌症和炎性疾病中的基因转录。
Protein-based therapeutics feature large interacting surfaces. Protein folding endows structural stability to localised surface epitopes, imparting high affinity and target specificity upon interactions with binding partners. However, short synthetic peptides with sequences corresponding to such protein epitopes are unstructured in water and promiscuously bind to proteins with low affinity and specificity. Here we combine structural stability and target specificity of proteins, with low cost and rapid synthesis of small molecules, towards meeting the significant challenge of binding coiled coil proteins in transcriptional regulation. By iteratively truncating a Jun-based peptide from 37 to 22 residues, strategically incorporating i→i+4 helix-inducing constraints, and positioning unnatural amino acids, we have produced short, water-stable, α-helical peptides that bind cFos. A three-dimensional NMR-derived structure for one peptide (24) confirmed a highly stable α-helix which was resistant to proteolytic degradation in serum. These short structured peptides are entropically pre-organized for binding with high affinity and specificity to cFos, a key component of the oncogenic transcriptional regulator Activator Protein-1 (AP-1). They competitively antagonized the cJun–cFos coiled-coil interaction. Truncating a Jun-based peptide from 37 to 22 residues decreased the binding enthalpy for cJun by ∼9 kcal/mol, but this was compensated by increased conformational entropy (TΔS ≤7.5 kcal/mol). This study demonstrates that rational design of short peptides constrained by α-helical cyclic pentapeptide modules is able to retain parental high helicity, as well as high affinity and specificity for cFos. These are important steps towards small antagonists of the cJun-cFos interaction that mediates gene transcription in cancer and inflammatory diseases.
登录
查看更多内容
影响因子：
3.3
作者：
Dixon, JM;Taniguchi, M;Lindsey, JS
通讯作者：
Lindsey, JS
影响因子：
15
作者：
Chapman, RN;Dimartino, G;Arora, PS
通讯作者：
Arora, PS
影响因子：
3
作者：
BROOKS, BR;BRUCCOLERI, RE;KARPLUS, M
通讯作者：
KARPLUS, M
DOI：
10.1074/jbc.m111.221267
发表时间：
2011-08-26
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Crooks RO;Rao T;Mason JM
通讯作者：
Mason JM
影响因子：
15
作者：
Kutchukian, Peter S.;Yang, Jae Shick;Shakhnovich, Eugene I.
通讯作者：
Shakhnovich, Eugene I.