Toward Understanding the Mechanism of Client-Selective Small Molecule Inhibitors of the Sec61 Translocon.

IF 2.3 4区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Molecular Recognition Pub Date : 2024-10-12 DOI:10.1002/jmr.3108

Nidhi Sorout, Volkhard Helms

引用次数: 0

Abstract

The Sec61 translocon mediates the translocation of numerous, newly synthesized precursor proteins into the lumen of the endoplasmic reticulum or their integration into its membrane. Recently, structural biology revealed conformations of idle or substrate-engaged Sec61, and likewise its interactions with the accessory membrane proteins Sec62, Sec63, and TRAP, respectively. Several natural and synthetic small molecules have been shown to block Sec61-mediated protein translocation. Since this is a key step in protein biogenesis, broad inhibition is generally cytotoxic, which may be problematic for a putative drug target. Interestingly, several compounds exhibit client-selective modes of action, such that only translocation of certain precursor proteins was affected. Here, we discuss recent advances of structural biology, molecular modelling, and molecular screening that aim to use Sec61 as feasible drug target.

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了解 Sec61 Translocon 的客户选择性小分子抑制剂的机制。

Sec61 转座子介导大量新合成的前体蛋白转座到内质网腔内或整合到内质网膜上。最近，结构生物学揭示了空闲或底物参与的 Sec61 的构象，以及它分别与附属膜蛋白 Sec62、Sec63 和 TRAP 的相互作用。一些天然和合成的小分子已被证明能阻断 Sec61 介导的蛋白质转运。由于这是蛋白质生物发生过程中的关键步骤，广泛的抑制作用通常具有细胞毒性，这可能会给药物靶点带来问题。有趣的是，有几种化合物表现出了客户选择性的作用模式，例如只有某些前体蛋白的转运受到影响。在此，我们讨论了结构生物学、分子建模和分子筛选方面的最新进展，旨在将 Sec61 作为可行的药物靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Molecular Recognition 生物-生化与分子生物学

CiteScore

4.60

自引率

3.70%

发文量

审稿时长

2.7 months

期刊介绍： Journal of Molecular Recognition (JMR) publishes original research papers and reviews describing substantial advances in our understanding of molecular recognition phenomena in life sciences, covering all aspects from biochemistry, molecular biology, medicine, and biophysics. The research may employ experimental, theoretical and/or computational approaches. The focus of the journal is on recognition phenomena involving biomolecules and their biological / biochemical partners rather than on the recognition of metal ions or inorganic compounds. Molecular recognition involves non-covalent specific interactions between two or more biological molecules, molecular aggregates, cellular modules or organelles, as exemplified by receptor-ligand, antigen-antibody, nucleic acid-protein, sugar-lectin, to mention just a few of the possible interactions. The journal invites manuscripts that aim to achieve a complete description of molecular recognition mechanisms between well-characterized biomolecules in terms of structure, dynamics and biological activity. Such studies may help the future development of new drugs and vaccines, although the experimental testing of new drugs and vaccines falls outside the scope of the journal. Manuscripts that describe the application of standard approaches and techniques to design or model new molecular entities or to describe interactions between biomolecules, but do not provide new insights into molecular recognition processes will not be considered. Similarly, manuscripts involving biomolecules uncharacterized at the sequence level (e.g. calf thymus DNA) will not be considered.