9VEQ

Crystal structure of Keap1 in complex with a small molecule inhibitor, KMN003

これはPDB形式変換不可エントリーです。

9VEQ の概要

• エントリーDOI: 10.2210/pdb9veq/pdb
• 分子名称: Kelch-like ECH-associated protein 1, 4-[1,4-bis[(4-ethoxyphenyl)sulfonylamino]naphthalen-2-yl]butanoic acid, FORMIC ACID, ... (4 entities in total)
• 機能のキーワード: nrf2 inhibitor, peptide binding protein, peptide binding protein-inhibitor complex, peptide binding protein/inhibitor
• 由来する生物種: Mus musculus (house mouse)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 64622.11

構造登録者

Ishida, H.,Osawa, M. (登録日: 2025-06-10, 公開日: 2025-11-12, 最終更新日: 2026-01-21)

主引用文献

Komeda, K.,Toyoshima, K.,Yasuda, D.,Ishida, H.,Kojima, K.,Osawa, M.,Hirano, T.,Ohe, T.,Tago, K.,Funakoshi-Tago, M.
KMN003 activates Nrf2 via disruption of the Keap1-Nrf2 interaction and p38-dependent transcriptional regulation.
Cell Signal., 137:112194-112194, 2026

PubMed Abstract: Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that plays a crucial role in cellular defenses against oxidative stress and inflammation. Under normal conditions, Kelch-like ECH-associated protein 1 (Keap1), a ubiquitin ligase adaptor, binds to Nrf2, facilitating its ubiquitination and subsequent degradation via the proteasome. In this study, we investigated the properties of KMN003, a novel Nrf2 activator specifically designed to stabilize Nrf2 by disrupting its interaction with Keap1. X-ray crystallographic analysis revealed that KMN003 binds to the DGR-Cul3 (DC) domain of Keap1, occupying the Nrf2 interaction site. An AlphaScreen assay further showed that KMN003 effectively inhibits the binding between the Keap1 DC domain and the DLG motif of Nrf2 (IC₅₀ = 300 nM). We also investigated the mechanism of Nrf2 activation by KMN003 and its anti-inflammatory properties using murine macrophage-like RAW264.7 cells. KMN003 significantly reduced the lipopolysaccharide (LPS)-induced production of nitric oxide, CCL2, and tumor necrosis factor-alpha (TNFα) as well as the mRNA expression of inducible nitric oxide synthase, CCL2, and TNFα, which are essential inflammatory markers. KMN003 strongly inhibited nuclear translocation and transcriptional activation of nuclear factor-kappa B (NF-κB), a central regulator of inflammatory gene expression. KMN003 did not affect the LPS-induced phosphorylation of ERK or JNK, but strongly induced p38 phosphorylation in the absence of the LPS stimulation. The inhibition of p38 with SB203580 blocked KMN003-induced Nrf2 transcriptional activation despite promoting Nrf2 accumulation. These results highlight KMN003 as a promising anti-inflammatory drug that selectively stabilizes and activates Nrf2 via the p38 pathway.

PubMed: 41489533
DOI: 10.1016/j.cellsig.2025.112194

実験手法

X-RAY DIFFRACTION (1.7 Å)