炭疽素诱导的蛋白酶体亢进及其分子机制

IF 2.3 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Biochemistry and Biophysics Reports Pub Date : 2024-09-23 DOI:10.1016/j.bbrep.2024.101830
Kotaro Sakamoto , Runa Fujimoto , Erina Kamiyama-Ando , Takatsugu Hirokawa
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引用次数: 0

摘要

最近,靶向蛋白质降解作为一种新的药物发现方法引起了越来越多的关注。这种方法旨在通过蛋白酶体等蛋白质降解系统诱导药物靶点降解,从而控制药物靶点的功能。与此同时,能增强蛋白酶体活性的化合物也备受关注。2023 年,我们报道了木质素家族的天然产物 anthricin(又称 4-deoxypodophyllotoxin)能增强蛋白酶体的活性。然而,这种增强是由于蛋白酶体表达的增加还是蛋白酶体功能的改善仍不清楚。在这项研究中,我们研究了花翠素及其类似物在增强蛋白酶体活性方面的结构-活性关系、花翠素对蛋白酶体相关基因表达的影响以及花翠素与蛋白酶体之间的直接结合。此外,我们还利用分子动力学(MD)模拟评估了蒽素与蛋白酶体之间的相互作用。结果表明,蒽素并不诱导蛋白酶体相关基因的表达,而是与蛋白酶体的β亚基结合,使催化位点的三个氨基酸残基(Thr1、Asp17和Lys33)的侧链靠拢,从而诱导蛋白酶体进入亢奋状态。据我们所知,这项研究首次在分子水平上提出了蒽素增强蛋白酶体活性的机制。这些发现有助于开发新的化学类型,通过调节蛋白酶体的活性来增强靶向蛋白降解剂的效果。
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Anthricin-induced hyperactive proteasome and its molecular mechanism
Recently, targeted protein degradation has attracted increasing interest as a new drug discovery approach. This method aims to control the function of drug targets by inducing their degradation through protein degradation systems such as the proteasome. Concurrently, compounds that enhance proteasome activity have also garnered attention. In 2023, we reported that anthricin (also known as 4-deoxypodophyllotoxin), a natural product that belongs to the lignan family, enhances proteasome activity. However, whether this enhancement was because of increased proteasome expression or improved proteasome function remains unclear. In this study, we investigated the structure–activity relationship of anthricin and its analogs in enhancing proteasome activity, the effects of anthricin on proteasome-related gene expression, and the direct binding between anthricin and the proteasome using pull-down assay. Moreover, we assessed the interaction between anthricin and the proteasome using molecular dynamics (MD) simulations. The results showed that anthricin does not induce proteasome-related gene expression, but instead binds to the β-subunit of the proteasome, bringing the side chains of three amino acid residues (Thr1, Asp17, and Lys33) at the catalytic site closer together, thereby inducing a hyperactive state. To the best of our knowledge, this study is the first to suggest the mechanism of proteasome activity enhancement by anthricin at the molecular level. The findings could contribute to the development of new chemotypes to enhance the effects of targeted protein degraders by regulating proteasome activity.
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来源期刊
Biochemistry and Biophysics Reports
Biochemistry and Biophysics Reports Biochemistry, Genetics and Molecular Biology-Biophysics
CiteScore
4.60
自引率
0.00%
发文量
191
审稿时长
59 days
期刊介绍: Open access, online only, peer-reviewed international journal in the Life Sciences, established in 2014 Biochemistry and Biophysics Reports (BB Reports) publishes original research in all aspects of Biochemistry, Biophysics and related areas like Molecular and Cell Biology. BB Reports welcomes solid though more preliminary, descriptive and small scale results if they have the potential to stimulate and/or contribute to future research, leading to new insights or hypothesis. Primary criteria for acceptance is that the work is original, scientifically and technically sound and provides valuable knowledge to life sciences research. We strongly believe all results deserve to be published and documented for the advancement of science. BB Reports specifically appreciates receiving reports on: Negative results, Replication studies, Reanalysis of previous datasets.
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