Kelch-like ECH-associated protein 1–Nuclear factor erythroid 2–related factor 2 protein–protein interface (Keap1–Nrf2 PPI)

The Keap1–Nrf2 protein–protein interface is a molecular interaction between Kelch-like ECH-associated protein 1 (Keap1) and nuclear factor erythroid 2–related factor 2 (Nrf2), critical for negative regulation of the cellular antioxidant response. Under normal conditions, Keap1 acts as a cytosolic substrate adaptor, binding Nrf2 via its Kelch domain at conserved ETGE and DLG motifs of Nrf2, targeting it for Cullin 3 (Cul3)–mediated ubiquitination and subsequent proteasomal degradation to maintain low Nrf2 levels[1][2][4]. In response to oxidative or electrophilic stress, modification of Keap1 cysteine residues leads to stabilization and accumulation of Nrf2, which translocates to the nucleus to activate genes involved in antioxidant defense, detoxification, and metabolic regulation[2][6]. The Keap1–Nrf2 interface has emerged as an important drug target: inhibiting this interaction (via PPI inhibitors) can upregulate protective responses and is under investigation for diseases involving oxidative stress and inflammation, including cancer and neurodegeneration[4][5][6]. Agents specifically targeting this protein–protein interface are being developed to provide greater safety and selectivity compared to traditional electrophilic Nrf2 activators[5][6].

Other names

Keap1–Nrf2 PPIKeap1–Nrf2 interfaceKelch domain of Keap1–Nrf2 interactionKeap1–Nrf2 protein–protein interaction

Inhibitors disrupt the Keap1–Nrf2 interaction, preventing Keap1-mediated ubiquitination and proteasomal degradation of Nrf2, thereby activating Nrf2-dependent gene transcription [5][6]. Some drugs act as electrophilic compounds modifying Keap1 cysteines, but PPI inhibitors work via specific interface binding with higher target selectivity [5].