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

The DOI matches its Crossref record; 69 of the 69 references it cites were found in a registry or an index.

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

Open access

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

DOI 10.1038/sj.emboj.7601243PMC PMC1538563

Open this paper in CoChat — free account

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.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

Integrity signals

Registry

Crossref · 10.1038/sj.emboj.7601243

Cites

69 of 69 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

1 retracted

RETRACTED ARTICLE: Genetic alterations of the NRP/B gene are associated with human brain tumors
Liang, X.-Q., Avraham, H. K., Jiang, S., & Avraham, S. (2004) · Oncogene · doi:10.1038/sj.onc.1207776 · Cited by 47
Retracted
Coot : model-building tools for molecular graphics
Emsley, P., & Cowtan, K. (2004) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444904019158 · Cited by 30,571
The PyMOL Molecular Graphics System
DeLano, W. L. (2002) · Medical Entomology and Zoology · Cited by 18,147
Refinement of Macromolecular Structures by the Maximum-Likelihood Method
Murshudov, G. N., Vagin, A. A., & Dodson, E. J. (1997) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444996012255 · Cited by 14,796
Oxidants, oxidative stress and the biology of ageing
Finkel, T., & Holbrook, N. J. (2000) · Nature · doi:10.1038/35041687 · Cited by 9,413
Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain
Itoh, K., Wakabayashi, N., Katoh, Y., Ishii, T., Igarashi, K., Engel, J. D., & Yamamoto, M. (1999) · Genes & Development · doi:10.1101/gad.13.1.76 · Cited by 3,634
Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2
Kobayashi, A., Kang, M.-I., Okawa, H., Ohtsuji, M., Zenke, Y., Chiba, T., Igarashi, K., & Yamamoto, M. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.16.7130-7139.2004 · Cited by 2,224
Pathways of Oxidative Damage
Imlay, J. A. (2003) · Annual Review of Microbiology · doi:10.1146/annurev.micro.57.030502.090938 · Cited by 2,201
Direct evidence that sulfhydryl groups of Keap1 are the sensors regulating induction of phase 2 enzymes that protect against carcinogens and oxidants
Dinkova-Kostova, A. T., Holtzclaw, W. D., Cole, R. N., Itoh, K., Wakabayashi, N., Katoh, Y., Yamamoto, M., & Talalay, P. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.172398899 · Cited by 1,947
Use of TLS parameters to model anisotropic displacements in macromolecular refinement
Winn, M., Isupov, M. N., & Murshudov, G. N. (2001) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444900014736 · Cited by 1,685

Show all 68 references

Sorted by citations

Items 301–400 of 627

The C-Terminal Domain of Nrf1 Negatively Regulates the Full-Length CNC-bZIP Factor and Its Shorter Isoform LCR-F1/Nrf1β; Both Are Also Inhibited by the Small Dominant-Negative Nrf1γ/δ Isoforms that Down-Regulate ARE-Battery Gene Expression
Zhang, Y., Qiu, L., Li, S., Xiang, Y., Chen, J., & Ren, Y. (2014) · PLoS ONE · doi:10.1371/journal.pone.0109159 · Cited by 25
Mechanisms Underlying Chemopreventive Effects of Flavonoids via Multiple Signaling Nodes within Nrf2-ARE and AhR-XRE Gene Regulatory Networks
Xiao, H., Lu, F.-L., Stewart, D., & Zhang, Y. (2013) · Current Chemical Biology · doi:10.2174/2212796811307020008 · Cited by 25
Co- and Post-Treatment with Lysine Protects Primary Fish Enterocytes against Cu-Induced Oxidative Damage
Li, X., Liu, Y., Jiang, W., Jiang, J., Wu, P., Zhao, J., Kuang, S., Tang, L. Y., Tang, W., Zhang, Y., et al. (2016) · PLoS ONE · doi:10.1371/journal.pone.0147408 · Cited by 26
“[63] reported that seven lysine residues located in Nrf2 play an important role in Keap1-dependent degradation.”
BackgroundSelf-citation
A novel biscoumarin compound ameliorates cerebral ischemia reperfusion-induced mitochondrial oxidative injury via Nrf2/Keap1/ARE signaling
Wang, J., Zhang, W., Lv, C., Wang, Y., Ma, B., Zhang, H., Fan, Z., Li, M., & Li, X. (2019) · Neuropharmacology · doi:10.1016/j.neuropharm.2019.107918 · Cited by 25
Self-citation
Impaired Integrity of DNA After Recovery From Inflammation Causes Persistent Dysfunction of Colonic Smooth Muscle
Choi, K., Chen, J., MITRA, S. P., & Sarna, S. K. (2011) · Gastroenterology · doi:10.1053/j.gastro.2011.06.074 · Cited by 25
WNK1 Interaction with KEAP1 Promotes NRF2 Stabilization to Enhance the Oxidative Stress Response in Hepatocellular Carcinoma
Li, L., Xie, D., Yu, S., Ma, M., Fan, K., Chen, J., Xiu, M., Xie, K., Li, Y., & Gao, Y. (2024) · Cancer Research · doi:10.1158/0008-5472.can-23-1167 · Cited by 24
TLR Signaling Prevents Hyperoxia-Induced Lung Injury by Protecting the Alveolar Epithelium from Oxidant-Mediated Death
Ballinger, M. N., Newstead, M. W., Zeng, X., Bhan, U., Horowitz, J. C., Moore, B. B., Pinsky, D. J., Flavell, R. A., & Standiford, T. J. (2012) · The Journal of Immunology · doi:10.4049/jimmunol.1103124 · Cited by 24
“phosphorylated (16–19), escapes Keap1-mediated degradation, and translocates into the nucleus (20) to initiate transcription of antioxidant genes (17).”
Background
Virtual Screening Expands the Non-Natural Amino Acid Palette for Peptide Optimization
Amarasinghe, K. N., Maria, L. D., Tyrchan, C., Eriksson, L. A., Sadowski, J., & Petrović, D. (2022) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.2c00193 · Cited by 24
Genetic, Transcriptomic, and Epigenetic Studies of HIV-Associated Neurocognitive Disorder
Levine, A. J., Panos, S. E., & Horvath, S. (2013) · JAIDS Journal of Acquired Immune Deficiency Syndromes · doi:10.1097/qai.0000000000000069 · Cited by 24
Pueraria lobata-derived peptides hold promise as a novel antioxidant source by mitigating ethanol-induced oxidative stress in HepG2 cells through regulating the Keap1/Nrf2 pathway
Liu, L., Liang, J., He, M., Jiang, B., Liu, J., Wu, J., Li, P., & Du, B. (2025) · Food Chemistry · doi:10.1016/j.foodchem.2025.145014 · Cited by 23
Structural mapping of Kelch13 mutations associated with artemisinin resistance in malaria
Singh, G. P., Goel, P., & Sharma, A. K. (2016) · Journal of Structural and Functional Genomics · doi:10.1007/s10969-016-9205-1 · Cited by 23
Connecting West and East
Ming, Z., Moalin, M., & Haenen, G. R. M. M. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20092333 · Cited by 24
Role of Nuclear Factor Erythroid 2 (Nrf2) in the Recovery of Long COVID-19 Using Natural Antioxidants: A Systematic Review
Muchtaridi, M., Amirah, S. R., Harmonis, J. A., & Ikram, E. H. K. (2022) · Antioxidants · doi:10.3390/antiox11081551 · Cited by 26
The vicious circle of UHRF1 down‐regulation and KEAP1 / NRF2 / HO ‐1 pathway impairment promotes oxidative stress‐induced endothelial cell apoptosis in diabetes
Guo, Z., Wan, X.-X., Luo, Y., Liang, F., Jiang, S., Yuan, X., & Mo, Z. (2022) · Diabetic Medicine · doi:10.1111/dme.15026 · Cited by 23
Tuning melatonin receptor subtype selectivity in oxadiazolone-based analogues: Discovery of QR2 ligands and NRF2 activators with neurogenic properties
Herrera‐Arozamena, C., Estrada, M., Pérez, C., Lagartera, L., Morales-Garcia, J. A., Pérez‐Castillo, A., Franco‐Gonzalez, J. F., Michalska, P., Duarte, P., Leon, R. M., et al. (2020) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2020.112090 · Cited by 23
“The binding site residues involved in the NRF2-KEAP1 interaction are very well known and have been reported by several authors [64].”
Background
Bioinformatics analyses provide insight into distant homology of the Keap1–Nrf2 pathway
Gaćeša, R., Dunlap, W. C., & Long, P. F. (2015) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2015.06.015 · Cited by 23
Machine learning methods for unveiling the potential of antioxidant short peptides in goat milk-derived proteins during in vitro gastrointestinal digestion
Du, A., Jia, W., & Zhang, R. (2024) · Journal of Dairy Science · doi:10.3168/jds.2024-24887 · Cited by 22
Activation, interaction and intimation of Nrf2 pathway and their mutational studies causing Nrf2 associated cancer
Sahu, M., & Jain, U. (2025) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2025.167764 · Cited by 24
Binding of Disordered Peptides to Kelch: Insights from Enhanced Sampling Simulations
Do, T. N., Choy, W., & Karttunen, M. (2015) · Journal of Chemical Theory and Computation · doi:10.1021/acs.jctc.5b00868 · Cited by 22
Antiaging function of Chinese pond turtle (Chinemys reevesii) peptide through activation of the Nrf2/Keap1 signaling pathway and its structure-activity relationship
Wang, Q., Yang, Z., Zhuang, J., Zhang, J., Shen, F., Yu, P., Zhong, H., & Feng, F. (2022) · Frontiers in Nutrition · doi:10.3389/fnut.2022.961922 · Cited by 22
Briarane-type diterpenoids, the inhibitors of osteoclast formation by interrupting Keap1-Nrf2 interaction and activating Nrf2 pathway
Qi, X., Zhang, X., Meng, J., Wu, J., Cheng, W., Huang, J., & Lin, W. (2022) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2022.114948 · Cited by 22
Identification of a PGXPP degron motif in dishevelled and structural basis for its binding to the E3 ligase KLHL12
Chen, Z., Wasney, G. A., Picaud, S., Filippakopoulos, P., Vedadi, M., D’Angiolella, V., & Bullock, A. N. (2020) · Open Biology · doi:10.1098/rsob.200041 · Cited by 21
Dendritic cells' death induced by contact sensitizers is controlled by Nrf2 and depends on glutathione levels
Ali, Z. E., Deloménie, C., Botton, J., Pallardy, M. J., & Kerdine‐Römer, S. (2017) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2017.02.014 · Cited by 24
Effects of bioactive constituents in the Traditional Chinese Medicinal formula Si–Wu–Tang on Nrf2 signaling and neoplastic cellular transformation
Liu, M. M., Huang, K. M., Qian, L., Chatterjee, P., Zhang, S., Li, R., Zhou, S., Wang, Z. K., Luo, Y., & Huang, Y. S. (2017) · Phytomedicine · doi:10.1016/j.phymed.2017.12.031 · Cited by 21
CUL3 and protein kinases: Insights from PLK1/KLHL22 interaction
Metzger, T., Kleiss, C., & Sumara, I. (2013) · Cell Cycle · doi:10.4161/cc.25369 · Cited by 21
Tussilagone inhibits dendritic cell functions via induction of heme oxygenase-1
Park, Y., Ryu, H. S., Lee, H. K., Kim, J. S., Yun, J., Kang, J. S., Hwang, B. Y., Hong, J. T., Kim, Y. S., & Han, S. (2014) · International Immunopharmacology · doi:10.1016/j.intimp.2014.07.023 · Cited by 21
Saucerneol D inhibits dendritic cell activation by inducing heme oxygenase-1, but not by directly inhibiting toll-like receptor 4 signaling
Ryu, H. S., Lee, H. K., Kim, J. S., Kim, Y. G., Pyo, M., Yun, J., Hwang, B. Y., Hong, J. T., Kim, Y. S., & Han, S. (2015) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2015.03.020 · Cited by 21
Nrf2
Kim, K. M., & Ki, S. H. (2017) · Elsevier eBooks · doi:10.1016/b978-0-12-804274-8.00028-x · Cited by 22
Phosphorylation of KLHL3 at serine 433 impairs its interaction with the acidic motif of WNK4: a molecular dynamics study
Wang, L., & Peng, J. (2016) · Protein Science · doi:10.1002/pro.3063 · Cited by 20
Jatamansinol from Nardostachys jatamansi: a multi-targeted neuroprotective agent for Alzheimer’s disease
Anupama, K. P., Olakkaran, S., Antony, A., & Gurushankara, H. P. (2021) · Journal of Biomolecular Structure and Dynamics · doi:10.1080/07391102.2021.2005681 · Cited by 20
“, 2004), and Keap1 (PDB ID2FLU) (Lo et al., 2006) (Figure 1) were collected from Protein Data Bank (RCSB PDB) (Burley et al.”
Method
Purification and Identification of Peptides from Hydrilla verticillata (Linn. f.) Royle with Cytoprotective and Antioxidative Effect against H2O2-Treated HepG2 Cells
Tang, Y., Liang, F., Yan, Y., Zeng, Y., Li, Y., & Zhou, R. (2024) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.3c09917 · Cited by 20
PYDDT, a novel phase 2 enzymes inducer, activates Keap1–Nrf2 pathway via depleting the cellular level of glutathione
Zhang, X., Zhao, X., & Ma, Z. (2010) · Toxicology Letters · doi:10.1016/j.toxlet.2010.08.011 · Cited by 20
Molecular models and mutational analyses of plant specifier proteins suggest active site residues and reaction mechanism
Brandt, W., Backenköhler, A., Schulze, E., Plock, A., Herberg, T., Roese, E., & Wittstock, U. (2013) · Plant Molecular Biology · doi:10.1007/s11103-013-0126-0 · Cited by 20
Screening and preparation of highly active antioxidant peptides of apricot and their inhibitory effect on ultraviolet radiation
Zhu, X., Zhang, X., Wang, Z., Ren, F., Zhu, X., Chen, B., Liu, H., & Wuyun, T. (2024) · Food Chemistry · doi:10.1016/j.foodchem.2024.141336 · Cited by 19
Oxidative Stress Amelioration of Novel Peptides Extracted from Enzymatic Hydrolysates of Chinese Pecan Cake
Zhang, J., Wu, S., Wang, Q., Yuan, Q., Li, Y., Reboredo‐Rodríguez, P., Varela‐López, A., He, Z., Wu, F., Hu, H., et al. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232012086 · Cited by 19
“Nrf2 16-mer peptide (2FLU ligand) established hydrogen bonds with Tyr-334, Ser-363, Arg-380, Asn-382, Arg-415, Arg-483, Ser-508, Gln-530, Ser555, and Ser-602 of Keap1 [19,41,42].”
Background
Natural products: protective effects against ischemia-induced retinal injury
He, Q., Xiao, L., Shi, Y., Li, W., & Xin, X. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1149708 · Cited by 19
“Fortunately, eukaryotic cells have established protective strategies to combat ROS by enhancing endogenous antioxidant production (Lo et al., 2006).”
Background
Nuclear Factor Erythroid 2 Related Factor 2 and Mitochondria Form a Mutually Regulating Circuit in the Prevention and Treatment of Metabolic Syndrome
Zhang, J., Lv, W., Zhang, G., Zeng, M., Cao, W., Su, J., Cao, K. J., & Liu, J. (2024) · Antioxidants and Redox Signaling · doi:10.1089/ars.2023.0339 · Cited by 22
“The binding of ETGE motif of Nrf2 and Keap1 can be prevented by hydrophobic and electro-philic interaction with Kelch pairing in Keap1 (Lo et al., 2006; Tong et al., 2007), as shown in Figure 3.”
Prediction of Binding Energy of Keap1 Interaction Motifs in the Nrf2 Antioxidant Pathway and Design of Potential High-Affinity Peptides
Karttunen, M., Choy, W., & Cino, E. A. (2018) · The Journal of Physical Chemistry B · doi:10.1021/acs.jpcb.8b03295 · Cited by 19
Anchor Residues Guide Form and Function in Grafted Peptides
Yin, H., Craik, D. J., & Wang, C. K. L. (2019) · Angewandte Chemie International Edition · doi:10.1002/anie.201901572 · Cited by 19
Identification of novel inhibitors of Keap1/Nrf2 by a promising method combining protein–protein interaction-oriented library and machine learning
Shimizu, Y., Yonezawa, T., Sakamoto, J., Furuya, T., Osawa, M., & Ikeda, K. (2021) · Scientific Reports · doi:10.1038/s41598-021-86616-1 · Cited by 20
An Integrated Molecular Grafting Approach for the Design of Keap1-Targeted Peptide Inhibitors
Yin, H., Huang, Y., Best, S. A., Sutherland, K. D., Craik, D. J., & Wang, C. K. L. (2021) · ACS Chemical Biology · doi:10.1021/acschembio.1c00388 · Cited by 19
Recent Advances in the Role of Nuclear Factor Erythroid-2-Related Factor 2 in Spinal Cord Injury: Regulatory Mechanisms and Therapeutic Options
Jiang, T., & He, Y. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.851257 · Cited by 19
Small molecule and peptide inhibitors of βTrCP and the βTrCP–NRF2 protein–protein interaction
Jaffry, U., & Wells, G. (2023) · Biochemical Society Transactions · doi:10.1042/bst20220352 · Cited by 18
Oleanolic acid alleviating ischemia-reperfusion injury in rat severe steatotic liver via KEAP1/NRF2/ARE
Pi, Y., Zuo, H., Wang, Y., Zheng, W., Zhou, H., Deng, L., & Song, H. (2024) · International Immunopharmacology · doi:10.1016/j.intimp.2024.112617 · Cited by 18
Design, Synthesis, and Initial Evaluation of Affinity-Based Small-Molecule Probes for Fluorescent Visualization and Specific Detection of Keap1
Lu, M., Zhou, H.-S., You, Q., & Jiang, Z. (2016) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6b00775 · Cited by 18
Ellagic acid inhibits proinflammatory intermediary manufacture by suppressing NF-κB/Akt, VEGF and activating Nrf-2/Caspase-3 signaling pathways in rat testicular damage: a new way for testicular damage cure and in silico approach
Aslan, A. N., Gök, Ö., Beyaz, S., Uslu, H., Erman, F., Erman, O., & Başpınar, S. (2022) · Toxicology Mechanisms and Methods · doi:10.1080/15376516.2022.2046668 · Cited by 17
“1997), Nrf-2 (Lo et al. 2006), Caspase-3 (Solania et al.”
MethodInfluential
Computational Prediction of Cyclic Peptide Structural Ensembles and Application to the Design of Keap1 Binders
Lopez, F., Miao, J., Damjanovic, J., Bischof, L., Braun, M. B., Ling, Y., Hartmann, M. D., Lin, Y., & Kritzer, J. A. (2023) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.3c01337 · Cited by 18
Rosuvastatin alleviates high-salt and cholesterol diet-induced cognitive impairment in rats via Nrf2–ARE pathway
Husain, I., Akhtar, M., Madaan, T., Abdin, M. Z., Islamuddin, M., & Najmi, A. K. (2018) · Redox Report · doi:10.1080/13510002.2018.1492774 · Cited by 17
“Higher the docking score indicates more the binding affinity [32,33].”
Background
Exploring new strategies for grafting binding peptides onto protein loops using a consensus‐designed tetratricopeptide repeat scaffold
Madden, S. K., Perez‐Riba, A., & Itzhaki, L. S. (2019) · Protein Science · doi:10.1002/pro.3586 · Cited by 17
“E79 of Nrf2 forms hydrogen bonds to R415, R483, and S508 of Keap1 whereas E82 hydrogen bonds to S363, N382, and R380 PDB ID 2FLU.(48)”
Background
BRUP‐1, an intracellular bilirubin modulator, exerts neuroprotective activity in a cellular Parkinson’s disease model
Kataura, T., Saiki, S., Ishikawa, K., Akamatsu, W., Sasazawa, Y., Hattori, N., & Imoto, M. (2020) · Journal of Neurochemistry · doi:10.1111/jnc.14997 · Cited by 17
Interactions of the major metabolite of the cancer chemopreventive drug oltipraz with cytochrome c: A novel pathway for cancer chemoprevention
Velayutham, M., Muthukumaran, R. B., Sostaric, J. Z., McCraken, J., Fishbein, J. C., & Zweier, J. L. (2007) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2007.06.022 · Cited by 17
Cryo-EM structure of the KLHL22 E3 ligase bound to an oligomeric metabolic enzyme
Teng, F., Wang, Y., Liu, M., Tian, S., Stjepanović, G., & Su, M.-Y. (2023) · Structure · doi:10.1016/j.str.2023.09.002 · Cited by 16
Involvement of the Keap1-Nrf2-ARE pathway in the antioxidant activity of sinomenine
Guan, T., Li, N., Xu, X., Xiong, D., Wang, B., Xiao, L., Yang, W., Chu, G., Yusuf, A., Zhang, J., et al. (2024) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2024.109928 · Cited by 16
Tumor suppressor KEAP1 promotes HSPA9 degradation, controlling mitochondrial biogenesis in breast cancer
Han, B., Zhen, F., Sun, Y., Sun, B., Wang, H., Liu, W., Huang, J., Liang, X., Wang, Y., Chen, X., et al. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.114507 · Cited by 18
Exploring the separation, characterization and antioxidant activity of proteins and peptides from selected seagrasses in Palk Bay region of Tamil Nadu in India
Arya, R., Abinaya, K., Sakthivelu, M., Thirumavalavan, M., Velmurugan, D., Anbu, P., & Pachaiappan, R. (2025) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2025.139606 · Cited by 16
Activation of anti-oxidant Nrf2 signaling by substituted trans stilbenes
Deck, L. M., Whalen, L. J., Hunsaker, L. A., Royer, R. E., & Jagt, D. L. V. (2017) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2017.01.005 · Cited by 16
Virtual screening identified natural Keap1-Nrf2 PPI inhibitor alleviates inflammatory osteoporosis through Nrf2-mir214-Traf3 axis
Hong, J., Shi, Z., Li, C., Ji, X., Li, S., Chen, Y., Jiang, G., Shi, M., Wang, W., Zhang, Y., et al. (2021) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2021.05.020 · Cited by 17
SH-29 and SK-119 Attenuates Air-Pollution Induced Damage by Activating Nrf2 in HaCaT Cells
Kahremany, S., Hofmann, L., Eretz-Kdosha, N., Silberstein, E., Gruzman, A., & Cohen, G. (2021) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph182312371 · Cited by 14
Rosmarinic Acid Ameliorates Dermatophagoides farinae Extract-Induced Atopic Dermatitis-like Skin Inflammation by Activating the Nrf2/HO-1 Signaling Pathway
Shim, K., Kim, H. J., Ji, K.-Y., Jung, D. H., Park, S. H., Song, H., Kim, T., & Kim, K. M. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252312737 · Cited by 15
Two Antihypertensive and Antioxidant Peptides Derived from Alaska Pollack ( Theragra chalcograma ) Skin: In Silico , In Vitro , and In Vivo Investigation
Li, J., Cai, D., Zhai, Y.-N., Wu, C., Zhang, H., Zhang, J., Liu, C., Liu, S., & Qu, J. (2025) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.5c00166 · Cited by 15
Pharmacological characterization of a novel peptide inhibitor of the Keap1-Nrf2 protein-protein interaction
Aparici, M., Bravo, M., Calama, E., García‐González, V., Domènech, T., Córdoba, M., Roger, I., Cortijo, J., Góngora‐Benítez, M., Paradís‐Bas, M., et al. (2022) · Biochemical Pharmacology · doi:10.1016/j.bcp.2022.115226 · Cited by 15
Targeting kelch-like (KLHL) proteins: achievements, challenges and perspectives
Zhou, Y., Zhang, Q., Zhao, Z., Hu, X., You, Q., & Jiang, Z. (2024) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2024.116270 · Cited by 15
Thermodynamic profiling of inhibitors of Nrf2:Keap1 interactions
Nasiri, H. R., Linge, S., & Ullmann, D. (2015) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2015.11.082 · Cited by 15
The bridge between cell survival and cell death: reactive oxygen species-mediated cellular stress
Acar, N. V., & Özgül, R. K. (2023) · EXCLI journal · doi:10.17179/excli2023-6221 · Cited by 19
Control of craniofacial and brain development by Cullin3-RING ubiquitin ligases: Lessons from human disease genetics
Asmar, A. J., Beck, D. B., & Werner, A. A. (2020) · Experimental Cell Research · doi:10.1016/j.yexcr.2020.112300 · Cited by 13
Novel iodinated quinazolinones bearing sulfonamide as new scaffold targeting radiation induced oxidative stress
Soliman, A. M., Mekkawy, M. H., Karam, H. M., Higgins, M., Dinkova‐Kostova, A. T., & Ghorab, M. M. (2021) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2021.128002 · Cited by 14
Symmetric Structures in the Universe of Protein Folds
Guerler, A., Wang, C. W., & Knapp, E. (2009) · Journal of Chemical Information and Modeling · doi:10.1021/ci900185z · Cited by 14
The role of modulation of antioxidant enzyme systems in the treatment of neurodegenerative diseases
Obuobi, S. A. O., Karatayev, S., Chai, C. L. L., Ee, P. L. R., & Mátyus, P. (2016) · Journal of Enzyme Inhibition and Medicinal Chemistry · doi:10.1080/14756366.2016.1205047 · Cited by 15
Isolation and characterization of thymoquinone from Nigella sativa essential oil: antioxidant and antibacterial activities, molecular modeling studies, and cytotoxic effects on lung cancer A549 cells
Erdoğan, Ü., Erbaş, S., Muhammed, M. T., Önem, E., Soyocak, A., & Ak, A. (2024) · Journal of Essential Oil Bearing Plants · doi:10.1080/0972060x.2024.2352418 · Cited by 13
“The crystallographic study reported that the various amino acids of Nrf2 peptide interacted to Keap1 via diverse interaction residues 31 .”
BackgroundInfluential
Structural Elucidation of Peptide Binding to KLHL-12, a Substrate Specific Adapter Protein in a Cul3-Ring E3 Ligase Complex
Zhao, B., Payne, W. G., Sai, J., Lu, Z., Olejniczak, E. T., & Fesik, S. W. (2020) · Biochemistry · doi:10.1021/acs.biochem.9b01073 · Cited by 13
NRF2 activator A-1396076 ameliorates inflammation in autoimmune disease models by inhibiting antigen dependent T cell activation
Goess, C., Terrillon, S., Mayo, M., Bousquet, P. F., Wallace, C. D., Hart, M., Mathieu, S., Twomey, R., Donnelly‐Roberts, D. L., Namovic, M. T., et al. (2020) · Journal of Translational Autoimmunity · doi:10.1016/j.jtauto.2020.100079 · Cited by 13
KEAP1 Cancer Mutants: A Large-Scale Molecular Dynamics Study of Protein Stability
Wilson, C. J., Chang, M., Karttunen, M., & Choy, W. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22105408 · Cited by 12
“The starting protein structure was prepared from the Neh2-Kelch crystal structure (PDB: 2FLU) [73] downloaded from the Protein Data Bank [74].”
BackgroundMethod
Discovery of a Kelch-like ECH-associated protein 1-inhibitory tetrapeptide and its structural characterization
Sogabe, S., Sakamoto, K., Kamada, Y., Kadotani, A., Fukuda, Y., & Sakamoto, J. (2017) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2017.03.038 · Cited by 15
Flavonoids Seen through the Energy Perspective
Li, Z., Zhang, M., Haenen, G. R. M. M., Vervoort, L., & Moalin, M. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms23010187 · Cited by 13
“Moreover, the soft energy can very efficiently turn on the protection sensor, KEAP1, to finally make more antioxidants [47,48].”
Background
Nrf2 in Host Defense: Over the Rainbow
Cho, H., Kwak, M., & Pi, J. (2013) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2013/975839 · Cited by 13
Isoliquiritigenin attenuates cisplatin-induced hearing loss and ototoxicity by activating the Keap1-Nrf2-ARE pathway
Chen, Y., Luo, X., Deng, Y., Zhu, G., Chu, X., Zhu, J., Shao, S., Zhang, L., Chen, X., Chen, Y., et al. (2025) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2025.10.004 · Cited by 12
Hijacking the unfolded protein response (UPR) pathway: Balancing viral infection and host cell survival
Chen, H., Liu, D., Hua, J., Wu, M., Hua, Y., Feng, C., He, Z., Moffett, P., & Zhang, K. (2025) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2025.111040 · Cited by 13
“PERK also contributes to oxidative defense through nuclear factor erythroid 2-related factor 2 (NRF2) activation (40).”
A ubiquitin-based effector-to-inhibitor switch coordinates early brain, craniofacial, and skin development
Asmar, A. J., Abrams, S. R., Hsin, J., Collins, J. C., Yazejian, R. M., Wu, Y., Cho, J., Doyle, A. D., Cinthala, S., Simon, M., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-40223-y · Cited by 11
Demethylcalabaxanthone from Garcinia mangostana Exerts Antioxidant Effects through the Activation of the Nrf2 Pathway as Assessed via Molecular Docking and Biological Evaluation
Vita, S. D., Masullo, M., Grambone, S., Bermejo‐Bescós, P., Piacente, S., & Bifulco, G. (2023) · Antioxidants · doi:10.3390/antiox12111980 · Cited by 12
“Ser363 and Asn414 Arg415 (2) Tyr334 and Tyr525 Gly364, Arg380, Gly462, Arg483, Ser508, Gly509, Gln530, Ser555, Ala556, Tyr572, Phe577, Ser602, and Gly603”
Background
Computational Assessment of Carotenoids as Keap1-Nrf2 Protein–Protein Interaction Inhibitors: Implications for Antioxidant Strategies
Medoro, A., Jafar, T. H., Sallustio, F., Scapagnini, G., Saso, L., & Davinelli, S. (2024) · Biochemistry (Moscow) · doi:10.1134/s0006297924100031 · Cited by 12
“This β-hairpin conformation is stabilized by a network of intramolecular hydrogen bonds involving the backbone atoms of residues Gln75, Asp77, Asp79, Thr80, Glu82, Leu89, and the sidechain atoms of residues Asp77 and Thr80 [33, 45].”
Germination affects structural and techno-functional properties of proteins from quinoa seeds with increased realease of antioxidant peptides by gastrointestinal digestion
He, Y., Deng, Z., Chai, T., Miao, Y., Liu, J., & Liu, H. (2024) · Food Chemistry · doi:10.1016/j.foodchem.2024.142532 · Cited by 13
Determinants, Discriminants, Conserved Residues - A Heuristic Approach to Detection of Functional Divergence in Protein Families
Bharatham, K., Zhang, Z. H., & Mihalek, I. (2011) · PLoS ONE · doi:10.1371/journal.pone.0024382 · Cited by 12
“The main descriptors for each test case - acquisition of interacting interface in a-lactalbumin [56], he specificity of interferon-a receptor for its favorite type of interferon, IGFBP5 specific binding to extracellular matrix [57], thrombin interface for thrombomodulin [58], and Kelch for Nrf2 [59] - are listed in pa…”
Background
Chirality-Driven Folding of Short β-Lactam Pseudopeptides
Aizpurua, J. M., Palomo, C., Balentová, E., Jiménez, A., Andreieff, E., Sagartzazu‐Aizpurua, M., Miranda, J. I., & Linden, A. (2012) · The Journal of Organic Chemistry · doi:10.1021/jo302368y · Cited by 12
Regulation of post-translational modifications of muskelin by protein kinase C
Prag, S., Arcangelis, A. D., Georges‐Labouesse, E., & Adams, J. C. (2006) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2006.09.003 · Cited by 12
PXDesign: Fast, Modular, and Accurate De Novo Design of Protein BindersPreprint
Protenix Team, Ren, M., Sun, J., Guan, J., Liu, C., Gong, C., Wang, Y. X., Wang, L., Cai, Q., Ma, W., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.08.15.670450 · Cited by 14
NRF2 Dysregulation and Therapeutic Insights Across Chronic Kidney Diseases
Lim, T. S. T., Ng, K. H., & Zhang, Y. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26157471 · Cited by 14
In-silico validation of novel therapeutic activities of withaferin a using molecular docking and dynamics studies
Ulhas, R. S., & Malaviya, A. (2022) · Journal of Biomolecular Structure and Dynamics · doi:10.1080/07391102.2022.2078410 · Cited by 11
Screening approaches for the identification of Nrf2-Keap1 protein-protein interaction inhibitors targeting hot spot residues
Asano, W., Hantani, R., Uhara, T., Debaene, F., Nomura, A., Yamaguchi, K., Adachi, T., Otake, K., Harada, K., & Hantani, Y. (2023) · SLAS DISCOVERY · doi:10.1016/j.slasd.2023.11.001 · Cited by 11
“Both the higher affinity ETGE peptide motif (protein data bank [PDB]: 2FLU) and the lower affinity DLG peptide motif (PDB: 2DYH) bind in the central cavity of the Kelch domain and interact with serine, arginine, and tyrosine side chains [13,14].”
Background
Computational analysis of protein–protein interactions of cancer drivers in renal cell carcinoma
Pei, J., Zhang, J., & Cong, Q. (2023) · FEBS Open Bio · doi:10.1002/2211-5463.13732 · Cited by 11
“NRF2 utilizes two small SLiMs in disordered regions (residues 17 – 40 and residues 69 – 84) to interact with the beta-propeller domain of KEAP1 [68,69].”
Background
Functional development of porcine spleen as a by-product of pig slaughterhouse: Preparation, identification and bioactive activities of a novel peptide
Liu, C., An, H.-X., & Liu, A. (2023) · Food Bioscience · doi:10.1016/j.fbio.2023.103448 · Cited by 11
An in vivo and in silico probing of the protective potential of betaine against sodium fluoride-induced neurotoxicity
Owumi, S. E., Oluwawibe, B. J., Chimezie, J., Babalola, J. O., Ogunyemi, O. M., Gyebi, G. A., Otunla, M. T., Altayyar, A., Arunsi, U. O., Irozuru, C. E., et al. (2024) · BMC Pharmacology and Toxicology · doi:10.1186/s40360-024-00812-z · Cited by 11
Targeted substrate degradation by Kelch controls the actin cytoskeleton during ring canal expansion
Hudson, A. M., Mannix, K. M., Gerdes, J. A., Kottemann, M. C., & Cooley, L. (2018) · Development · doi:10.1242/dev.169219 · Cited by 11
“In contrast, Keap1, a more distantly related BBK protein, targets its substrate Nrf2 for ubiquitylation through a high-affinity interaction with a short DxETGE sequence (Lo et al., 2006).”
Background
Nuclear factor erythroid 2-related factor 2 agonist protects retinal ganglion cells in glutamate excitotoxicity retinas
An, Y., Li, H., Wang, M., Xia, Z., Ding, L., & Xia, X. (2022) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2022.113378 · Cited by 11
Synthesis, spectroscopic, in vitro, in vivo biological evaluation, and in silico docking analysis of new meloxicam metal complexes
Samra, M. M., & Basra, M. A. R. (2022) · Applied Organometallic Chemistry · doi:10.1002/aoc.7002 · Cited by 10
Isolation, identification and activity analysis of antioxidant peptides from rice wine lees
Wu, Y., Zhang, X., Cui, H., Li, H., & Hu, X. (2023) · Journal of Food Measurement & Characterization · doi:10.1007/s11694-023-02244-5 · Cited by 10
Synthesis and Bioevaluation of New Stable Derivatives of Chrysin-8-C-Glucoside That Modulate the Antioxidant Keap1/Nrf2/HO-1 Pathway in Human Macrophages
Ávila‐Román, J., Quevedo-Tinoco, L., Oliveros-Ortiz, A. J., García-Gil, S., Rodríguez‐García, G., Motilva, V., Gómez‐Hurtado, M. A., & Talero, E. (2024) · Pharmaceuticals · doi:10.3390/ph17101388 · Cited by 10
“Chemical shift ( δ ) values are expressed”
Background
Covalent Inhibitors of KEAP1 with Exquisite Selectivity
Fejes, I., Markacz, P., Tatai, J., Rudas, M., Dunkel, P., Gyuris, M., Nyerges, M., Provost, N., Duvivier, V., Delerive, P., et al. (2024) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.4c02019 · Cited by 10
Structural mimicry of UM171 and neomorphic cancer mutants co-opts E3 ligase KBTBD4 for HDAC1/2 recruitment
Chen, Z., Chi, G., Balo, T., Chen, X., Montes, B. R., Clifford, S. C., D’Angiolella, V., Szabo, T., Kiss, A., Novak, T., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-58350-z · Cited by 10
Structural basis of Nrf2 activation by flavonolignans from silymarin
Bello, M. (2022) · Journal of Molecular Graphics and Modelling · doi:10.1016/j.jmgm.2022.108393 · Cited by 10
Comparative in silico and in vitro study of the stability and biological activity of an octapeptide from microalgae Isochrysis zhanjiangensis and its truncated short peptide
Lin, L., He, Y., Liu, Y., Hong, P., Zhou, C., Sun, S., & Qian, Z. (2023) · Food & Function · doi:10.1039/d3fo00129f · Cited by 11

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

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

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

Abstract

Overview

Integrity signals

Verification

Claims the paper makes

Claims other papers make about this one

Self-check

Citations

Cites

Cited by

Related

Metadata

Record

About these checks