New strategies to inhibit KEAP1 and the Cul3-based E3 ubiquitin ligases. (23rd January 2014)

• Record Type: Journal Article
• Authors: Canning, Peter; Bullock, Alex N.
• Is Part Of: Biochemical Society transactions. Volume 42:Number 1(2014)
• Page Start: 103
• Page End: 107
• Publication Date: 2014-01-23
• Subjects: antioxidant response -- cancer -- cell signalling -- degradation -- drug design -- ubiquitylation; Biochemistry -- Congresses; 572
• DOI: 10.1042/BST20130215
• Languages: English
• ISSNs: 0300-5127

Abstract

Abstract : E3 ubiquitin ligases that direct substrate proteins to the ubiquitin–proteasome system are promising, though largely unexplored drug targets both because of their function and their remarkable specificity. CRLs [Cullin–RING (really interesting new gene) ligases] are the largest group of E3 ligases and function as modular multisubunit complexes constructed around a Cullin-family scaffold protein. The Cul3-based CRLs uniquely assemble with BTB (broad complex/tramtrack/bric-à-brac) proteins that also homodimerize and perform the role of both the Cullin adapter and the substrate-recognition component of the E3. The most prominent member is the BTB–BACK (BTB and C-terminal Kelch)–Kelch protein KEAP1 (Kelch-like ECH-associated protein 1), a master regulator of the oxidative stress response and a potential drug target for common conditions such as diabetes, Alzheimer's disease and Parkinson's disease. Structural characterization of BTB–Cul3 complexes has revealed a number of critical assembly mechanisms, including the binding of an N-terminal Cullin extension to a bihelical '3-box' at the C-terminus of the BTB domain. Improved understanding of the structure of these complexes should contribute significantly to the effort to develop novel therapeutics targeted to CRL3-regulated pathways.