Targeting Cullin-RING E3 ubiquitin ligases for drug discovery: structure, assembly and small-molecule modulation.
Targeting Cullin-RING E3 ubiquitin ligases for drug discovery: structure, assembly and small-molecule modulation.
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DOI：
10.1042/bj20141450
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发表时间：
2015-05-01
期刊：
影响因子：
--
通讯作者：
Ciulli A
中科院分区：
文献类型：
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作者：
Bulatov E;Ciulli A
在过去的十年中，泛素-蛋白酶体系统已经成为开发新疗法的有效靶点。E3泛素连接酶是特别有吸引力的靶标，因为它们赋予泛素系统底物特异性。CRL [Cullin-RING（真正有趣的新基因）E3泛素连接酶]引起了特别的关注，是E3最大的家族。CRL使用底物受体、衔接子、Cullin支架和RING盒蛋白组装成功能性多亚基复合物。靶向CRL的药物发现越来越重要，因为越来越多的证据表明这些酶在不同的生物过程和人类疾病中发挥重要作用，包括癌症，其中CRL及其底物通常作为肿瘤抑制因子或致癌基因发挥作用。在本综述中，我们提供了一个帐户的组装和结构的CRL复合物，并概述了目前的状态领域的小分子抑制剂和调节剂的CRL活性的现有知识。CRL亚基，组件和全尺寸的复合物，单独或结合小分子和底物肽的晶体结构的报告的全面概述，包括在内。这些信息提供了越来越多的机会，以帮助合理的化学探针和潜在的小分子治疗靶向CRL的结构为基础的设计。
In the last decade, the ubiquitin–proteasome system has emerged as a valid target for the development of novel therapeutics. E3 ubiquitin ligases are particularly attractive targets because they confer substrate specificity on the ubiquitin system. CRLs [Cullin–RING (really interesting new gene) E3 ubiquitin ligases] draw particular attention, being the largest family of E3s. The CRLs assemble into functional multisubunit complexes using a repertoire of substrate receptors, adaptors, Cullin scaffolds and RING-box proteins. Drug discovery targeting CRLs is growing in importance due to mounting evidence pointing to significant roles of these enzymes in diverse biological processes and human diseases, including cancer, where CRLs and their substrates often function as tumour suppressors or oncogenes. In the present review, we provide an account of the assembly and structure of CRL complexes, and outline the current state of the field in terms of available knowledge of small-molecule inhibitors and modulators of CRL activity. A comprehensive overview of the reported crystal structures of CRL subunits, components and full-size complexes, alone or with bound small molecules and substrate peptides, is included. This information is providing increasing opportunities to aid the rational structure-based design of chemical probes and potential small-molecule therapeutics targeting CRLs.