4CXI

BTB domain of KEAP1

4CXI の概要

• エントリーDOI: 10.2210/pdb4cxi/pdb
• 関連するPDBエントリー: 4CXJ 4CXT
• 分子名称: KELCH-LIKE ECH-ASSOCIATED PROTEIN 1 (2 entities in total)
• 機能のキーワード: transcription
• 由来する生物種: HOMO SAPIENS (HUMAN)
• 細胞内の位置: Cytoplasm: Q14145
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 15293.65

構造登録者

Cleasby, A.,Yon, J.,Day, P.J.,Richardson, C.,Tickle, I.J.,Williams, P.A.,Callahan, J.F.,Carr, R.,Concha, N.,Kerns, J.K.,Qi, H.,Sweitzer, T.,Ward, P.,Davies, T.G. (登録日: 2014-04-07, 公開日: 2014-06-18, 最終更新日: 2023-12-20)

主引用文献

Cleasby, A.,Yon, J.,Day, P.J.,Richardson, C.,Tickle, I.J.,Williams, P.A.,Callahan, J.F.,Carr, R.,Concha, N.,Kerns, J.K.,Qi, H.,Sweitzer, T.,Ward, P.,Davies, T.G.
Structure of the Btb Domain of Keap1 and its Interaction with the Triterpenoid Antagonist Cddo.
Plos One, 9:98896-, 2014

PubMed Abstract: The protein Keap1 is central to the regulation of the Nrf2-mediated cytoprotective response, and is increasingly recognized as an important target for therapeutic intervention in a range of diseases involving excessive oxidative stress and inflammation. The BTB domain of Keap1 plays key roles in sensing environmental electrophiles and in mediating interactions with the Cul3/Rbx1 E3 ubiquitin ligase system, and is believed to be the target for several small molecule covalent activators of the Nrf2 pathway. However, despite structural information being available for several BTB domains from related proteins, there have been no reported crystal structures of Keap1 BTB, and this has precluded a detailed understanding of its mechanism of action and interaction with antagonists. We report here the first structure of the BTB domain of Keap1, which is thought to contain the key cysteine residue responsible for interaction with electrophiles, as well as structures of the covalent complex with the antagonist CDDO/bardoxolone, and of the constitutively inactive C151W BTB mutant. In addition to providing the first structural confirmation of antagonist binding to Keap1 BTB, we also present biochemical evidence that adduction of Cys 151 by CDDO is capable of inhibiting the binding of Cul3 to Keap1, and discuss how this class of compound might exert Nrf2 activation through disruption of the BTB-Cul3 interface.

PubMed: 24896564
DOI: 10.1371/JOURNAL.PONE.0098896

実験手法

X-RAY DIFFRACTION (2.35 Å)