PDF(Pubmed)
Abstract：
Protein homeostasis is a tightly conserved process that is regulated through the ubiquitin proteasome system (UPS) in a ubiquitin-independent or ubiquitin-dependent manner. Over the past two decades, the proteasome has become an excellent therapeutic target through inhibition of the catalytic core particle, inhibition of subunits responsible for recognizing and binding ubiquitinated proteins, and more recently, through targeted protein degradation using proteolysis targeting chimeras (PROTACs). The majority of the developed inhibitors of the proteasome\'s core particle rely on gaining selectivity through binding interactions within the unprimed substrate channel. Although this has allowed for selective inhibitors and chemical probes to be generated for the different proteasome isoforms, much remains unknown about the interactions that could be harnessed within the primed substrate channel to increase potency or selectivity. Herein, we discuss small molecules that interact with the primed substrate pocket and how their differences may give rise to altered activity. Taking advantage of additional interactions with the primed substrate pocket of the proteasome could allow for the generation of improved chemical tools for perturbing or monitoring proteasome activity.
摘要：
蛋白质稳态是一个紧密保守的过程，通过泛素蛋白酶体系统（UPS）以不依赖泛素或依赖泛素的方式进行调节。在过去的二十年里，蛋白酶体已经成为一个极好的治疗靶点通过抑制催化核心颗粒,抑制负责识别和结合泛素化蛋白的亚基，最近，通过使用蛋白水解靶向嵌合体(PROTACs)的靶向蛋白质降解。大多数已开发的蛋白酶体核心颗粒抑制剂依赖于通过未引发底物通道内的结合相互作用获得选择性。尽管这允许针对不同的蛋白酶体同工型产生选择性抑制剂和化学探针,关于可以在引发的底物通道内利用以增加效力或选择性的相互作用，仍然未知。在这里，我们讨论了与引发的底物袋相互作用的小分子，以及它们的差异如何引起活性的改变。利用与蛋白酶体的引发的底物袋的额外相互作用可以允许产生用于扰乱或监测蛋白酶体活性的改进的化学工具。
