{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T20:51:12Z","timestamp":1778100672986,"version":"3.51.4"},"reference-count":46,"publisher":"Portland Press Ltd.","issue":"1","license":[{"start":{"date-parts":[[2019,7,25]],"date-time":"2019-07-25T00:00:00Z","timestamp":1564012800000},"content-version":"vor","delay-in-days":2009,"URL":"http:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2014,2,1]]},"abstract":"<jats:p>E3 ubiquitin ligases that direct substrate proteins to the ubiquitin\u2013proteasome system are promising, though largely unexplored drug targets both because of their function and their remarkable specificity. CRLs [Cullin\u2013RING (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-\u00e0-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\u2013BACK (BTB and C-terminal Kelch)\u2013Kelch 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\u2013Cul3 complexes has revealed a number of critical assembly mechanisms, including the binding of an N-terminal Cullin extension to a bihelical \u20183-box\u2019 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.<\/jats:p>","DOI":"10.1042\/bst20130215","type":"journal-article","created":{"date-parts":[[2014,1,23]],"date-time":"2014-01-23T12:09:46Z","timestamp":1390478986000},"page":"103-107","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["New strategies to inhibit KEAP1 and the Cul3-based E3 ubiquitin ligases"],"prefix":"10.1042","volume":"42","author":[{"given":"Peter","family":"Canning","sequence":"first","affiliation":[{"name":"Structural Genomics Consortium, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7DQ, U.K."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alex\u00a0N.","family":"Bullock","sequence":"additional","affiliation":[{"name":"Structural Genomics Consortium, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7DQ, U.K."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"288","published-online":{"date-parts":[[2014,1,23]]},"reference":[{"key":"2021111720074423900_B1","doi-asserted-by":"crossref","first-page":"2727","DOI":"10.1073\/pnas.95.6.2727","article-title":"The ubiquitin\u2013proteasome pathway: the complexity and myriad functions of proteins death","volume":"95","author":"Ciechanover","year":"1998","journal-title":"Proc. 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