Gorelik Maryna, Sidhu Sachdev S
Banting and Best Dept. of Medical Research and the Dept. of Molecular Genetics Terrence Donnelly Center for Cellular and Biomolecular Research, University of Toronto 160 College Street Toronto ON Canada M5S 3E1.
Bioeng Transl Med. 2017 Mar;2(1):31-42. doi: 10.1002/btm2.10044. Epub 2016 Nov 14.
The ubiquitin proteasome system (UPS) has garnered much attention due to its potential for the development of therapeutics. Following a successful clinical application of general proteasome inhibitors much effort has been devoted to targeting individual UPS components including E3 enzymes and deubiquitinases that control specificity of ubiquitination. Our group has developed a novel approach for targeting the UPS proteins using engineered ubiquitin variants (Ubvs). These drug-like proteins can serve as valuable tools to study biological function of UPS components and assist in the development of small molecules for clinical use. In this review, we summarize studies of Ubvs targeting members of three major families, including deubiquitinases, HECT E3 ligases, and CRL E3 ligases. In particular, we focus on Ubv binding mechanisms, structural studies, and effects on enzyme function. Furthermore, new insights gained from the Ubvs are discussed in the context of small molecule studies.
泛素蛋白酶体系统（UPS）因其在治疗药物开发方面的潜力而备受关注。在通用蛋白酶体抑制剂成功应用于临床后，人们致力于靶向单个UPS组件，包括控制泛素化特异性的E3酶和去泛素化酶。我们的团队开发了一种使用工程化泛素变体（Ubvs）靶向UPS蛋白的新方法。这些类药物蛋白可作为研究UPS组件生物学功能的有价值工具，并有助于开发临床使用的小分子药物。在本综述中，我们总结了针对三个主要家族成员的Ubvs的研究，包括去泛素化酶、HECT E3连接酶和CRL E3连接酶。特别地，我们关注Ubv的结合机制、结构研究以及对酶功能的影响。此外，还在小分子研究的背景下讨论了从Ubvs获得的新见解。
