Activators and Inhibitors of NRF2: A Review of Their Potential for Clinical Development

Figure 1

Domain structures of NRF2 and KEAP1. (a) Domain structure of NRF2. NRF2 possesses six highly conserved domains called NRF2-ECH homology (Neh) domains [167]. The functional role of each Neh domain is specified. Within the Neh2 domain, the low-affinity (DLG) and high-affinity (ETGE) binding domains to KEAP1 are zoomed in. (b) Domain structure of a KEAP1 monomer showing the position of cysteine residues. The N-terminal BTB (bric-a-brac, tramtrack, broad complex) domain participates in homodimerization and binding to CUL3/RBX1. The C-terminal region, DGR (double glycine repeat) domain, contains a double glycine repeat called Kelch repeat that binds NRF2-Neh2 domain. The intervening region (IVR/LR) connects BTB and DGR domains and is particularly rich in redox-sensitive cysteine residues. Red and blue cysteine residues in KEAP1 are the most relevant for electrophile reactivity. This figure has been modified and extended from [168] to highlight the degradation domains in NRF2 and the cysteines of KEAP1.

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