人类雌激素相关受体γ的 C 端自结合螺旋肽可被一类新型合理设计的多肽拮抗剂作为药物靶标。

IF 3.4 3区 化学 Q2 CHEMISTRY, MULTIDISCIPLINARY
Zilong Li, Yue Peng, Haiyang Ye, Yunyi Zhang, Peng Zhou
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引用次数: 0

摘要

雌激素相关受体γ(ERRγ)被认为是癌症、炎症和代谢紊乱的潜在治疗靶点。ERRγ含有一个与配体结合结构域(LBD)C端相连的调节性AF2螺旋尾,它是一种自结合肽(SBP),可作为分子开关,通过分别与ERRγ LBD表面的AF2结合位点结合或解除结合,动态调节受体在活性和非活性状态之间的交替。传统的ERRγ调节剂都是小分子化学配体,从作用机制上可分为激动剂和反向激动剂;激动剂以激动构象将AF2稳定在ABS位点上,而反向激动剂则将AF2锁定在该位点之外,从而在很大程度上取消ERRγ的转录活性。本文描述了一类ERRγ多肽拮抗剂,它们能与原生AF2竞争ABS位点,从而阻断AF2与ERRγ LBD结构域结合的活性状态。自我抑制肽来自覆盖 AF2 区域的 SBP,我们期望它能通过减少其内在无序性和重新结合时的熵代价,有效地重新结合到 ABS 位点。为此,我们采用了碳氢订书机技术,在自我抑制肽的 N 端、中间或 C 端区域的 [i, i + 4] - 锚点残基对上架设了一座全碳氢桥。正如所预期的那样,研究发现钉钉肽是ERRγ LBD结构域的良好结合剂,能有效地与原生AF2螺旋尾竞争ERRγ ABS位点,与AF2对该位点的结合模式基本相似,并与该位点形成多种非共价相互作用,从而赋予结构域-肽复合物稳定性和特异性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

The C-terminal self-binding helical peptide of human estrogen-related receptor γ can be druggably targeted by a novel class of rationally designed peptidic antagonists

The C-terminal self-binding helical peptide of human estrogen-related receptor γ can be druggably targeted by a novel class of rationally designed peptidic antagonists

Orphan nuclear estrogen-related receptor γ (ERRγ) has been recognized as a potential therapeutic target for cancer, inflammation and metabolic disorder. The ERRγ contains a regulatory AF2 helical tail linked C-terminally to its ligand-binding domain (LBD), which is a self-binding peptide (SBP) and serves as molecular switch to dynamically regulate the receptor alternation between active and inactive states by binding to and unbinding from the AF2-binding site on ERRγ LBD surface, respectively. Traditional ERRγ modulators are all small-molecule chemical ligands that can be classified into agonists and inverse agonists in terms of their action mechanism; the agonists stabilize the AF2 in ABS site with an agonist conformation, while the inverse agonists lock the AF2 out of the site to largely abolish ERRγ transcriptional activity. Here, a class of ERRγ peptidic antagonists was described to compete with native AF2 for the ABS site, thus blocking the active state of AF2 binding to ERRγ LBD domain. Self-inhibitory peptide was derived from the SBP-covering AF2 region and we expected it can rebind potently to the ABS site by reducing its intrinsic disorder and entropy cost upon the rebinding. Hydrocarbon stapling was employed to do so, which employed an all-hydrocarbon bridge across the [i, i + 4]-anchor residue pair in the N-terminal, middle or C-terminal region of the self-inhibitory peptide. As might be expected, it is revealed that the stapled peptides are good binders of ERRγ LBD domain and can effectively compete with the native AF2 helical tail for ERRγ ABS site, which exhibit a basically similar binding mode with AF2 to the site and form diverse noncovalent interactions with the site, thus conferring stability and specificity to the domain–peptide complexes.

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来源期刊
CiteScore
6.60
自引率
3.30%
发文量
247
审稿时长
1.7 months
期刊介绍: This distinguished journal publishes articles concerned with all aspects of computational chemistry: analytical, biological, inorganic, organic, physical, and materials. The Journal of Computational Chemistry presents original research, contemporary developments in theory and methodology, and state-of-the-art applications. Computational areas that are featured in the journal include ab initio and semiempirical quantum mechanics, density functional theory, molecular mechanics, molecular dynamics, statistical mechanics, cheminformatics, biomolecular structure prediction, molecular design, and bioinformatics.
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