title: Structural basis of Keap1 interactions with Nrf2.
abstract: Keap1 is a highly redox-sensitive member of the BTB-Kelch family that assembles with the Cul3 protein to form a Cullin-RING E3 ligase complex for the degradation of Nrf2. Oxidative stress disables Keap1, allowing Nrf2 protein levels to accumulate for the transactivation of critical stress response genes. Consequently, the Keap1-Nrf2 system is extensively pursued for the development of protein-protein interaction inhibitors that will stabilize Nrf2 for therapeutic effect in conditions of neurodegeneration, inflammation, and cancer. Here we review current progress toward the structure determination of Keap1 and its protein complexes with Cul3, Nrf2 substrate, and small-molecule antagonists. Together the available structures establish a rational three-dimensional model to explain the two-site binding of Nrf2 as well as its efficient ubiquitination.
authors.affiliation: Structural Genomics Consortium, University of Oxford, Old Road Campus, Oxford OX3 7DQ, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Canning
authors.affiliation: Structural Genomics Consortium, University of Oxford, Old Road Campus, Oxford OX3 7DQ, UK.
authors.forename: Fiona J
authors.initials: FJ
authors.lastname: Sorrell
authors.affiliation: Structural Genomics Consortium, University of Oxford, Old Road Campus, Oxford OX3 7DQ, UK. Electronic address: alex.bullock@sgc.ox.ac.uk.
authors.forename: Alex N
authors.initials: AN
authors.lastname: Bullock
mesh_terms: D000818:Animals; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D051267:NF-E2-Related Factor 2 / Q000737:chemistry* / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D051267:NF-E2-Related Factor 2
keywords: BTB; Cullin; Free radicals; Keap1; Kelch; Nrf2; Ubiquitin