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Rational design and chemical modification of TEAD coactivator peptides to target hippo signaling pathway against gastrointestinal cancers
Journal of Receptors and Signal Transduction ( IF 2.8 ) Pub Date : 2020-09-10 , DOI: 10.1080/10799893.2020.1818093
Shuxia Gao 1 , Yingchao Wang 1 , Lijuan Ji 1
Affiliation  

Abstract

Human Hippo signaling pathway has been recognized as a new and promising therapeutic target of gastrointestinal cancers, which is regulated by the intermolecular recognition between the TEA domain (TEAD) transcription factor and its prime coactivators. The coactivator proteins adopt two hotspot sites, namely α-helix and Ω-loop, to interact with TEAD. Here, we demonstrate that both the α-helix and Ω-loop peptides cannot maintain in structured state when splitting from the full-length coactivator proteins; they exhibit a large intrinsic disorder in free state that prevents the coactivator peptide recognition by TEAD. Rational design is used to optimize the interfacial residues of coactivator α-helix peptides, which can effectively improve the favorable direct readout effect upon the peptide binding to TEAD. Chemical modification is employed to constrain the free α-helix peptide into native ordered conformation. The method introduces an all-hydrocarbon bridge across i and i + 4 residues to stabilize the helical structure of a free coactivator peptide, which can considerably reduce the unfavorable indirect readout effect upon the peptide binding to TEAD. The all-hydrocarbon bridge is designed to point out of the TEAD–peptide complex interface, which would not disrupt the direct intermolecular interaction between the TEAD and peptide. Therefore, the stapling only improves peptide affinity, but does not alter peptide specificity, to TEAD. Affinity assay confirms that the binding potency of coactivator α-helix peptides is improved substantially by >5-fold upon the rational design and chemical modification. Structural analysis reveals that the optimized/stapled peptides can form diverse nonbonded interactions such as hydrogen bonds and hydrophobic contacts with TEAD, thus conferring stability and specificity to the TEAD–peptide complex systems.



中文翻译:

TEAD共激活肽的合理设计和化学修饰靶向河马信号通路对抗胃肠癌

摘要

人类 Hippo 信号通路已被认为是胃肠道癌症的一个新的和有前景的治疗靶点,它受 TEA 域 (TEAD) 转录因子与其主要共激活因子之间的分子间识别的调节。共激活蛋白采用两个热点位点,即 α-螺旋和 Ω-环,与 TEAD 相互作用。在这里,我们证明了从全长共激活蛋白分裂时,α-螺旋和 Ω-环肽都不能保持结构化状态;它们在游离状态下表现出很大的内在紊乱,阻止了 TEAD 对共激活肽的识别。采用合理设计优化共激活因子α-螺旋肽的界面残基,可有效提高肽与TEAD结合后的有利直接读出效果。化学修饰用于将游离 α-螺旋肽限制为天然有序构象。该方法引入了一个全烃桥跨越 + 4 个残基以稳定游离共激活肽的螺旋结构,这可以显着降低肽与 TEAD 结合时不利的间接读出效应。全烃桥被设计为指向 TEAD-肽复合物界面,这不会破坏 TEAD 和肽之间的直接分子间相互作用。因此,装订仅提高肽亲和力,但不会改变肽对 TEAD 的特异性。亲和力测定证实,在合理设计和化学修饰后,共激活因子 α-螺旋肽的结合效力显着提高了 > 5 倍。结构分析表明,优化/钉合的肽可以形成多种非键合相互作用,例如氢键和与 TEAD 的疏水接触,

更新日期:2020-09-10
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