Abstract
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.
Highlights
In the last decade the field of the ubiquitin–proteasome system (UPS) has witnessed increasing attention of the scientific community, especially as a result of the award of the 2004 Nobel Prize in Chemistry to Aaron Ciechanover, Avram Hershko and Irwin Rose for the discovery of ubiquitin-mediated protein degradation [1]
We focus on current knowledge concerning the structure and assembly of Cullin–really interesting new gene (RING) E3 ubiquitin ligase (CRL) complexes
Given the relatively large number of published crystal structures of CRL1Skp2 components individually or in complex with other proteins (Supplementary Table S1), we propose that a structurebased drug design approach would be attractive for future development of potent inhibitors
Summary
In the last decade the field of the UPS (ubiquitin–proteasome system) has witnessed increasing attention of the scientific community, especially as a result of the award of the 2004 Nobel Prize in Chemistry to Aaron Ciechanover, Avram Hershko and Irwin Rose for the discovery of ubiquitin-mediated protein degradation [1]. The human genome encodes two E1-activating enzymes, 37 E2-conjugating enzymes and over 600 E3 ubiquitin ligases [4]. An isopeptide bond between the ε-amino group of a substrate lysine residue and the C-terminal glycine residue of ubiquitin is formed via E3 ligase-mediated catalysis, and between Ub molecules to form poly-Ub chains. As a result of this three-step conjugating cascade, ubiquitinated substrates can be recognized and degraded by the 26S proteasome in an ATP-dependent manner or downstream cell signalling responses are triggered [5,6]. Protein ubiquitination is reversible and the isopeptide bond can be hydrolysed by protease enzymes called deubiquitinases (DUBs), of which over 80 have been identified in the human genome [7].
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