4IN4

Crystal structure of cpd 15 bound to Keap1 Kelch domain

4IN4 の概要

• エントリーDOI: 10.2210/pdb4in4/pdb
• 関連するPDBエントリー: 4IQK
• 分子名称: Kelch-like ECH-associated protein 1, PHOSPHATE ION, 2-({5-[(2,4-dimethylphenyl)sulfonyl]-6-oxo-1,6-dihydropyrimidin-2-yl}sulfanyl)-N-[2-(trifluoromethyl)phenyl]acetamide, ... (4 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: 3
• 化学式量合計: 101780.53

構造登録者

Silvian, L.,Marcotte, D. (登録日: 2013-01-03, 公開日: 2013-05-15, 最終更新日: 2023-09-20)

主引用文献

Marcotte, D.,Zeng, W.,Hus, J.C.,McKenzie, A.,Hession, C.,Jin, P.,Bergeron, C.,Lugovskoy, A.,Enyedy, I.,Cuervo, H.,Wang, D.,Atmanene, C.,Roecklin, D.,Vecchi, M.,Vivat, V.,Kraemer, J.,Winkler, D.,Hong, V.,Chao, J.,Lukashev, M.,Silvian, L.
Small molecules inhibit the interaction of Nrf2 and the Keap1 Kelch domain through a non-covalent mechanism.
Bioorg.Med.Chem., 21:4011-4019, 2013

PubMed Abstract: Keap1 binds to the Nrf2 transcription factor to promote its degradation, resulting in the loss of gene products that protect against oxidative stress. While cell-active small molecules have been identified that modify cysteines in Keap1 and effect the Nrf2 dependent pathway, few act through a non-covalent mechanism. We have identified and characterized several small molecule compounds that specifically bind to the Keap1 Kelch-DC domain as measured by NMR, native mass spectrometry and X-ray crystallography. One compound upregulates Nrf2 response genes measured by a luciferase cell reporter assay. The non-covalent inhibition strategy presents a reasonable course of action to avoid toxic side-effects due to non-specific cysteine modification.

PubMed: 23647822
DOI: 10.1016/j.bmc.2013.04.019

実験手法

X-RAY DIFFRACTION (2.59 Å)