New strategies to inhibit KEAP1 and the Cul3-based E3 ubiquitin ligases.
Biochem Soc Trans
; 42(1): 103-7, 2014 Feb.
Article
em En
| MEDLINE
| ID: mdl-24450635
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Proteínas Culina
/
Peptídeos e Proteínas de Sinalização Intracelular
Limite:
Humans
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article