Cited by 627Genomics, phytochemicals, and oxidative stressUbiquitin and proteasome pathwaysRedox biology and oxidative stress

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Structure of the Keap1:Nrf2 interface provides mechanistic insight into Nrf2 signaling

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Lo, Shih‐Ching, Li, Xuchu, Henzl, Michael T, Beamer, Lesa J, Hannink, Mark·2006·The EMBO Journal

DOI 10.1038/sj.emboj.7601243PMC PMC1538563

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Abstract

Keap1 is a BTB-Kelch substrate adaptor protein that regulates steady-state levels of Nrf2, a bZIP transcription factor, in response to oxidative stress. We have determined the structure of the Kelch domain of Keap1 bound to a 16-mer peptide from Nrf2 containing a highly conserved DxETGE motif. The Nrf2 peptide contains two short antiparallel beta-strands connected by two overlapping type I beta-turns stabilized by the aspartate and threonine residues. The beta-turn region fits into a binding pocket on the top face of the Kelch domain and the glutamate residues form multiple hydrogen bonds with highly conserved residues in Keap1. Mutagenesis experiments confirmed the role of individual amino acids for binding of Nrf2 to Keap1 and for Keap1-mediated repression of Nrf2-dependent gene expression. Our results provide a detailed picture of how a BTB-Kelch substrate adaptor protein binds to its cognate substrate and will enable the rational design of novel chemopreventive agents.

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Binding of disordered proteins to a protein hub
Cino, E. A., Killoran, R. C., Karttunen, M., & Choy, W. (2013) · Scientific Reports · doi:10.1038/srep02305 · Cited by 33
“Simulated annealing was performed on each structure and resulting conformations that did not resemble the Neh2 domain site 1 region bound to the Kelch domain (PDB id: 2FLU) were used as starting structures 30 .”
Influential
A novel strategy to activate cytoprotective genes in the injured brain
Zhao, J., Redell, J. B., Moore, A. N., & Dash, P. K. (2011) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2011.03.046 · Cited by 33
“Immunoprecipitation and structural analysis studies have shown that the DEETGE motif is critical for Nrf2-Keap1 interaction and that synthetic peptides containing the DEETGE sequence can disrupt Nrf2-Keap1 interaction in vitro [8].”
Background
The instability of the BTB-KELCH protein Gigaxonin causes Giant Axonal Neuropathy and constitutes a new penetrant and specific diagnostic test
Boizot, A., Talmat-Amar, Y., Morrogh, D., Kuntz, N. L., Halbert, C., Chabrol, B., Houlden, H., Stojkovic, T., Schulman, B. A., Rautenstrauss, B. W., et al. (2014) · Acta Neuropathologica Communications · doi:10.1186/2051-5960-2-47 · Cited by 33
“Very interestingly, the level of Gigaxonin in heterozygous individuals ranges from [35,2-59,9] or [36,3-63,4]% of wild type Gigaxonin using tubulin or GAPDH normalizators, respectively.”
Background
Natural bioactive flavonoids as promising agents in alleviating exercise-induced fatigue
Liu, Y., Shen, X., Sha, M.-X., 冯兹阁, & Liu, Y. (2023) · Food Bioscience · doi:10.1016/j.fbio.2023.102360 · Cited by 32
Crystal-contact engineering to obtain a crystal form of the Kelch domain of human Keap1 suitable for ligand-soaking experiments
Hörer, S., Reinert, D. J., Ostmann, K., Hoevels, Y., & Nar, H. (2013) · Acta Crystallographica Section F Structural Biology and Crystallization Communications · doi:10.1107/s174430911301124x · Cited by 32
“The binding mode of the peptide used in this study is consistent with the binding mode reported by Lo and coworkers (PDB entry 2flu; Lo et al., 2006).”
BackgroundMethod
SETD6 is a negative regulator of oxidative stress response
Chen, A., Feldman, M., Vershinin, Z., & Levy, D. (2016) · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2016.01.003 · Cited by 30
Dimerization Controls Marburg Virus VP24-dependent Modulation of Host Antioxidative Stress Responses
Johnson, B., Li, J., Adhikari, J., Edwards, M. R., Zhang, H., Schwarz, T. M., Leung, D. W., Basler, C. F., Gross, M. L., & Amarasinghe, G. K. (2016) · Journal of Molecular Biology · doi:10.1016/j.jmb.2016.07.020 · Cited by 31
“These residues correspond to the previously identified Kelch interacting loop (K-Loop) (amino acids 202–219) [8], which contains the sequence DIEPCCGE [26].”
Background
Keap1–MCM3 interaction is a potential coordinator of molecular machineries of antioxidant response and genomic DNA replication in metazoa
Tamberg, N., Tahk, S., Koit, S., Kristjuhan, K., Kasvandik, S., Kristjuhan, A., & Ilves, I. (2018) · Scientific Reports · doi:10.1038/s41598-018-30562-y · Cited by 32
Ginnalin A Binds to the Subpockets of Keap1 Kelch Domain To Activate the Nrf2-Regulated Antioxidant Defense System in SH-SY5Y Cells
Zhang, Z., Peng, L., Fu, Y., Wang, W., Wang, P., & Zhou, F. (2021) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.0c00713 · Cited by 31
Structural and biochemical characterization establishes a detailed understanding of KEAP1-CUL3 complex assembly
Adamson, R. J., Payne, N. C., Bartual, S. G., Mazitschek, R., & Bullock, A. N. (2023) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2023.04.021 · Cited by 30
“Oxidative and electrophilic stress induce cysteine modifications that disrupt KEAP1 function, allowing NRF2 to accumulate for the trans-activation of stress-response genes [8 – 10].”
Influential
Antioxidant and Anti-inflammatory Activity of Sea Cucumber ( Holothuria scabra) Active Compounds against KEAP1 and iNOS Protein
Wargasetia, T. L., Ratnawati, H., Widodo, N., & Widyananda, M. H. (2023) · Bioinformatics and Biology Insights · doi:10.1177/11779322221149613 · Cited by 30
Targeting the Interplay Between Autophagy and the Nrf2 Pathway in Parkinson’s Disease with Potential Therapeutic Implications
Liu, M., Liu, S., Lin, Z.-H., Chen, X., Jiao, Q., Du, X., & Jiang, H. F. (2025) · Biomolecules · doi:10.3390/biom15010149 · Cited by 32
“Among these, the BTB, IVR, and DGR domains are particularly notable as the primary functional domains of Keap1 [174].”
Combined Peptide and Small-Molecule Approach toward Nonacidic THIQ Inhibitors of the KEAP1/NRF2 Interaction
Ontoria, J. M., Biancofiore, I., Fezzardi, P., Ferrigno, F., Torrente, E., Colarusso, S., Bianchi, E., Andreini, M., Patsilinakos, A., Kempf, G., et al. (2020) · ACS Medicinal Chemistry Letters · doi:10.1021/acsmedchemlett.9b00594 · Cited by 30
Mechanism of Cullin3 E3 Ubiquitin Ligase Dimerization
Choo, Y. Y., & Hagen, T. (2012) · PLoS ONE · doi:10.1371/journal.pone.0041350 · Cited by 30
New strategies to inhibit KEAP1 and the Cul3-based E3 ubiquitin ligases
Canning, P., & Bullock, A. N. (2014) · Biochemical Society Transactions · doi:10.1042/bst20130215 · Cited by 29
Optimization of linear and cyclic peptide inhibitors of KEAP1-NRF2 protein-protein interaction
Colarusso, S., Simone, D. D., Frattarelli, T., Andreini, M., Cerretani, M., Missineo, A., Moretti, D., Tambone, S., Kempf, G., Augustin, M. A., et al. (2020) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2020.115738 · Cited by 29
Purification and identification of antioxidant and angiotensin converting enzyme-inhibitory peptides from Guangdong glutinous rice wine
Guo, J., Lu, A., Sun, Y., Liu, B., Zhang, J., Zhang, L., Huang, P., Yang, A., Li, Z., Cao, Y., et al. (2022) · LWT · doi:10.1016/j.lwt.2022.113953 · Cited by 29
Novel β-Propeller of the BTB-Kelch Protein Krp1 Provides a Binding Site for Lasp-1 That Is Necessary for Pseudopodial Extension
Gray, C. H., McGarry, L., Spence, H. J., Riboldi‐Tunnicliffe, A., & Ozanne, B. W. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.023259 · Cited by 30
Myrosinase-treated glucoerucin is a potent inducer of the Nrf2 target gene heme oxygenase 1 — studies in cultured HT-29 cells and mice
Wagner, A. E., Sturm, C., Piegholdt, S., Wolf, I. M. A., Esatbeyoglu, T., Nicola, G. R. D., Iori, R., & Rimbach, G. H. (2015) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2015.01.004 · Cited by 29
“It is suggested that, under basal conditions, the Keap1/Cul3/ Rbx-Nrf2 complex is also present in the nucleus and, together with additional negative regulators (e.g., Bach1 and Src subfamily A members), degrades Nrf2 [37].”
BackgroundInfluential
Perfluoroarene-based peptide macrocycles that inhibit the Nrf2/Keap1 interaction
Steel, R., O'Connell, M. A., & Searcey, M. (2018) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2018.03.003 · Cited by 29
Phenyl Bis-Sulfonamide Keap1-Nrf2 Protein–Protein Interaction Inhibitors with an Alternative Binding Mode
Georgakopoulos, N., Talapatra, S., Dikovskaya, D., Dayalan Naidu, S., Higgins, M., Gatliff, J., Ayhan, A., Nikoloudaki, R., Schaap, M., Valko, K., et al. (2022) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.2c00457 · Cited by 33
Cyclic Peptide Keap1–Nrf2 Protein–Protein Interaction Inhibitors: Design, Synthesis, and In Vivo Treatment of Acute Lung Injury
Zou, J., Yan, J., Lu, Y., Zhou, Y., Zhang, K., Han, Q., Han, D., Gai, C., Chai, X., Zhao, Q., et al. (2024) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.4c00065 · Cited by 28
A facile strategy for the construction of a phage display cyclic peptide library for the selection of functional macrocycles
Xiang, H., Bai, L., Zhang, X., Dan, T., Cheng, P., Yang, X., Ai, H., Li, K., & Lei, X. (2024) · Chemical Science · doi:10.1039/d4sc03207a · Cited by 28
Peptide design to control protein–protein interactions
Wier, S. P. V., & Beekman, A. M. (2025) · Chemical Society Reviews · doi:10.1039/d4cs00243a · Cited by 34
Cullin 4-DCAF Proteins in Tumorigenesis
Zhou, Z., Song, X., Wavelet, C. M., & Wan, Y. (2020) · Advances in experimental medicine and biology · doi:10.1007/978-981-15-1025-0_15 · Cited by 29
Perspectives on the Clinical Development of NRF2-Targeting Drugs
Lastra, D., Fernández-Ginés, R., Manda, G., & Cuadrado, A. (2020) · Handbook of experimental pharmacology · doi:10.1007/164_2020_381 · Cited by 29
Cyanidin-3-O-glucoside and its metabolite protocatechuic acid ameliorate 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) induced cytotoxicity in HepG2 cells by regulating apoptotic and Nrf2/p62 pathways
Zhao, L., Zhou, N., Zhang, H., Pan, F., Ai, X., Wang, Y., Hao, S., & Wang, C. (2021) · Food and Chemical Toxicology · doi:10.1016/j.fct.2021.112582 · Cited by 28
Nrf2 Pathway and Autophagy Crosstalk: New Insights into Therapeutic Strategies for Ischemic Cerebral Vascular Diseases
Hu, Y. H., Luo, Y., & Zheng, Y. (2022) · Antioxidants · doi:10.3390/antiox11091747 · Cited by 29
An updated patent review of Nrf2 activators (2020-present)
Zhao, Z., Dong, R., Cui, K., You, Q., & Jiang, Z. (2023) · Expert Opinion on Therapeutic Patents · doi:10.1080/13543776.2023.2178299 · Cited by 28
Actin Cytoskeletal Organization in Drosophila Germline Ring Canals Depends on Kelch Function in a Cullin-RING E3 Ligase
Hudson, A. M., Mannix, K. M., & Cooley, L. (2015) · Genetics · doi:10.1534/genetics.115.181289 · Cited by 27
“This work was funded by NIH R01 GM043301 grant to L.C. K.M.M. was supported in part by the National Institute of General Medical Sciences NIH training grant T32 GM007223.”
Background
Medicinal Chemistry Insights into the Development of Small-Molecule Kelch-Like ECH-Associated Protein 1-Nuclear Factor Erythroid 2-Related Factor 2 (Keap1–Nrf2) Protein–Protein Interaction Inhibitors
Zhao, Z., Dong, R., You, Q., & Jiang, Z. (2023) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.3c00712 · Cited by 28
Radiomodulatory effect of a non-electrophilic NQO1 inducer identified in a screen of new 6, 8-diiodoquinazolin-4(3H)-ones carrying a sulfonamide moiety
Soliman, A. M., Karam, H. M., Mekkawy, M. H., Higgins, M., Dinkova‐Kostova, A. T., & Ghorab, M. M. (2020) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2020.112467 · Cited by 27
“The binding site of Kelch domain has been reported to have five subpockets: P1, P2, P3, P4 and P5 [64].”
Background
Regulation of Cell Proliferation and Nrf2-Mediated Antioxidant Defense: Conservation of Keap1 Cysteines and Nrf2 Binding Site in the Context of the Evolution of KLHL Family
Shilovsky, G. A., & Dibrova, D. V. (2023) · Life · doi:10.3390/life13041045 · Cited by 27
A cell-active cyclic peptide targeting the Nrf2/Keap1 protein–protein interaction
Iegre, J., Krajčovičová, S., Gunnarsson, A., Wissler, L., Käck, H., Łuchniak, A., Tångefjord, S., Narjes, F., & Spring, D. R. (2023) · Chemical Science · doi:10.1039/d3sc04083f · Cited by 26
Dynamic molecular architecture and substrate recruitment of cullin3–RING E3 ligase CRL3KBTBD2
Hu, Y., Zhang, Z., Mao, Q., Zhang, X., Hao, A., Xun, Y., Wang, Y., Han, L., Zhan, W., Liu, Q., et al. (2024) · Nature Structural & Molecular Biology · doi:10.1038/s41594-023-01182-6 · Cited by 26
“The Kelch domain has been shown to be involved in substrate recognition in SPOP and KEAP1 proteins 44,45 .”
Advances in KEAP1-based PROTACs as emerging therapeutic modalities: Structural basis and progress
Chen, J., Feng, D., Zhu, R., Li, H., & Chen, L. (2025) · Redox Biology · doi:10.1016/j.redox.2025.103781 · Cited by 29
“C loops [35,57].”
NRF2 in dermo‐cosmetic: From scientific knowledge to skin care products
Frantz, M., Rozot, R., & Marrot, L. (2022) · BioFactors · doi:10.1002/biof.1907 · Cited by 30
“This is also confirmed by the increase in skin sensitization reactions in Nrf2 knock-out mice,215 indicating that allergic skin inflammation induced by chemical sensitizers is controlled by the transcription factor Nrf2.”
BackgroundInfluential
Engineering a genetically encoded competitive inhibitor of the KEAP1–NRF2 interaction via structure-based design and phage display
Guntas, G., Lewis, S. M., Mulvaney, K. M., Cloer, E. W., Tripathy, A., Lane, T. R., Major, M. B., & Kuhlman, B. A. (2015) · Protein Engineering Design and Selection · doi:10.1093/protein/gzv055 · Cited by 26
“The Kelch domain of KEAP1was expressed using a pET15b-based expression plasmid with a N-terminal His-tag followed by a thrombin cleavage site (Lo et al., 2006).”
BackgroundMethodInfluential

Authors: Lo, S., Li, X., Henzl, M. T., Beamer, L. J., & Hannink, M.
Affiliations: University of Missouri (US)
Corresponding author: Beamer, Lesa J
Hannink, Mark
ORCID: Lo, Shih‐Ching
Beamer, Lesa J
Hannink, Mark
Venue: The EMBO Journal
Publisher: Springer Science and Business Media LLC
Published: 2006-08-03
Volume: 25
Issue: 15
Pages: 3605-3617
ISSN: 0261-4189 (ISSN-L)
1460-2075
DOI: 10.1038/sj.emboj.7601243
PMC: PMC1538563
OpenAlex: W2141982524
Cited by: 604
References: 68
Citations by year: 2026: 66 · 2025: 66 · 2024: 44 · 2023: 48 · 2022: 47 · 2021: 36 · 2020: 35 · 2019: 23 · 2018: 22 · 2017: 21 · 2016: 25 · 2015: 25 · 2014: 22 · 2013: 34 · 2012: 22
FWCI: 4.63
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springernature.com/gp/researchers/text-and-data-mining (tdm)
www.springernature.com/gp/researchers/text-and-data-mining (vor)
Locations: The EMBO Journal (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health
National Cancer Institute (P50CA103130)
National Center for Complementary and Integrative Health (AT003899, R01AT003899)
Lawrence Berkeley National Laboratory
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
Keywords: Keap1, Nrf2, Kelch domain, protein-protein interaction, beta-turn, oxidative stress response, chemoprevention, protein structure
MeSH terms: Kelch-Like ECH-Associated Protein 1, Amino Acid Sequence, Animals, Binding Sites, Cells, Cultured, Chlorocebus aethiops, Humans, Models, Molecular, Molecular Sequence Data, Phosphorylation, Protein Binding, Protein Conformation, Signal Transduction, Conserved Sequence, Protein Structure, Tertiary, Dimerization, COS Cells, Amino Acid Motifs, Intracellular Signaling Peptides and Proteins, NF-E2-Related Factor 2

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Structure of the Keap1:Nrf2 interface provides mechanistic insight into Nrf2 signaling

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