Department of Chemistry, University of Toronto , Toronto, ON M5S 3H6, Canada.
Department of Chemical and Physical Sciences, University of Toronto Mississauga , Mississauga, ON L5L 1C6, Canada.
J Med Chem. 2018 Jan 25;61(2):405-421. doi: 10.1021/acs.jmedchem.6b01346. Epub 2017 Feb 28.
The labeling of proteins with ubiquitin/ubiquitin-like (Ubl) proteins is crucial for several physiological processes and in the onset of various diseases. Recently, targeting ubiquitin protein labeling has shifted toward the use of allosteric mechanisms over classical activity-based approaches. Allosteric enzyme regulation offers the potential for greater selectivity and has demonstrated less susceptibility to acquired resistance often associated with active site inhibitors. Furthermore, the isoform diversity among E1 activating, E2 conjugating, E3 ligase, and deubiquitinating (DUB) enzymes offers an ideal platform for modulating activity via allostery. Herein, we have reviewed allosteric inhibitors of the ubiquitin E1-E2-E3 and DUB enzymatic cascade developed over the past decade with a focus on their mechanisms of action. We have highlighted the advantages as well as the challenges associated with designing allosteric modulators of the ubiquitin labeling machinery, and the future promise in targeting these systems using allosteric approaches.
蛋白质与泛素/泛素样（Ubl）蛋白的连接标签对于多种生理过程和各种疾病的发生都至关重要。最近，针对泛素蛋白标记的靶点已经从经典的基于活性的方法转移到别构机制。别构酶调节具有更高选择性的潜力，并且表现出对获得性耐药性的敏感性降低，而获得性耐药性通常与活性位点抑制剂相关。此外，E1 激活酶、E2 连接酶、E3 连接酶和去泛素化（DUB）酶之间的同工型多样性为通过别构作用调节活性提供了理想的平台。本文综述了过去十年中开发的泛素 E1-E2-E3 和 DUB 酶级联的别构抑制剂，重点介绍了它们的作用机制。我们强调了设计泛素标记机制的别构调节剂的优势和挑战，以及使用别构方法靶向这些系统的未来前景。
