Structural basis for Cul3 protein assembly with the BTB-Kelch family of E3 ubiquitin ligases
Open accessAbstract
Cullin-RING ligases are multisubunit E3 ubiquitin ligases that recruit substrate-specific adaptors to catalyze protein ubiquitylation. Cul3-based Cullin-RING ligases are uniquely associated with BTB adaptors that incorporate homodimerization, Cul3 assembly, and substrate recognition into a single multidomain protein, of which the best known are BTB-BACK-Kelch domain proteins, including KEAP1. Cul3 assembly requires a BTB protein "3-box" motif, analogous to the F-box and SOCS box motifs of other Cullin-based E3s. To define the molecular basis for this assembly and the overall architecture of the E3, we determined the crystal structures of the BTB-BACK domains of KLHL11 both alone and in complex with Cul3, along with the Kelch domain structures of KLHL2 (Mayven), KLHL7, KLHL12, and KBTBD5. We show that Cul3 interaction is dependent on a unique N-terminal extension sequence that packs against the 3-box in a hydrophobic groove centrally located between the BTB and BACK domains. Deletion of this N-terminal region results in a 30-fold loss in affinity. The presented data offer a model for the quaternary assembly of this E3 class that supports the bivalent capture of Nrf2 and reveals potential new sites for E3 inhibitor design.
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Keap1 contains three functional domains: the N-terminal BTB domain mediates homodimerization and contributes to Cul3 interaction, the IVR contains key reactive cysteine residues through which Nrf2 activity is regulated, and the C-terminal Kelch domain is important for Nrf2 binding.
“Accordingly, Keap1 contains three functional domains (Figure 5). The N-terminal BTB (broad complex, tramtrack, and bric à brac) domain mediates Keap1 homodimerization and contributes to its interaction with Cul3 [68]. Additional Cul3 interaction is provided by a 3-box motif found within the proximal part of the intervening region (IVR) [67]. The IVR contains key reactive cysteine residues through”
From Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease (2022) · cites this paper as [67]
BTB-containing E3 ligases are typically distinguished by a 3-box motif that enables high-affinity binding of Cullin 3.
“BTB-containing E3 ligases are typically distinguished by the presence of a 3-box motif that enables high-affinity binding of Cullin 3 (refs 74,75 ).”
From Targeted protein degradation: expanding the toolbox (2019) · cites this paper as [74]
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“After KEAP1, the best characterized protein is KLHL12, which modulates COPII assembly for collagen export (27) and also ubiquitylates both the dopamine D4 receptor (28) and dishevelled (29).”
Kelch-like homologue 9 mutation is associated with an early onset autosomal dominant distal myopathy
Çırak, S., von Deimling, F., Sachdev, S., Errington, W. J., Herrmann, R., Bönnemann, C. G., Brockmann, K., Hinderlich, S., Lindner, T. H., Steinbrecher, A., et al. (2010) · Brain · doi:10.1093/brain/awq108 · Cited by 75 · cited 1× · see citing works
“Mutations in the BTB-Kelch proteins KLHL3, KLHL7, and KLHL9 are additionally associated with hypertension (24), retinitis pigmentosa (25), and distal myopathy (26), respectively, although their corresponding substrates have yet to be identified.”
High‐Level Expression and Purification of Recombinant SCF Ubiquitin Ligases
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“To establish the molecular basis for Cul3 interaction, we adopted a split and express strategy for soluble protein expression (53).”
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 29 · see citing works
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The KEAP1-NRF2 system: a thiol-based sensor-effector apparatus for maintaining redox homeostasis
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The Molecular Mechanisms Regulating the KEAP1-NRF2 Pathway
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The whole-genome landscape of medulloblastoma subtypes
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Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease
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“Cul3 assembly requires a “3-box” motif that is characteristic of BTB-Kelch proteins [67].”
BackgroundInfluentialTargeted protein degradation: expanding the toolbox
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“A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript protein-protein interaction domain; an intervening region (IVR); a C-terminal doubleglycine repeat (DGR) domain (that consists of six subdomains, each of which contains a distinctive Gly-Gly motif, and is sometimes called the Kelch-repeat…”
InfluentialStructural basis of Keap1 interactions with Nrf2
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Self-citationThe integrated landscape of driver genomic alterations in glioblastoma
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“Although one study reports that one Cul3 protein binds to a homodimer of Keap1 (37), another report shows that two Cul3 proteins bind to a Keap1 homodimer (38).”
BackgroundDeshmukh, P. H., Unni, S., Krishnappa, G., & Padmanabhan, B. (2016) · Biophysical Reviews · doi:10.1007/s12551-016-0244-4 · Cited by 397 · see citing works
Keap1, the cysteine-based mammalian intracellular sensor for electrophiles and oxidants
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The KEAP1-NRF2 pathway: Targets for therapy and role in cancer
Adinolfi, S., Patinen, T., Deen, A. J., Pitkänen, S., Härkönen, J., Kansanen, E., Küblbeck, J., & Levonen, A. (2023) · Redox Biology · doi:10.1016/j.redox.2023.102726 · Cited by 301 · see citing works
Characterizations of Three Major Cysteine Sensors of Keap1 in Stress Response
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Medulloblastomics revisited: biological and clinical insights from thousands of patients
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Molecular Mechanism of Cellular Oxidative Stress Sensing by Keap1
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“To date, the KEAP1 and NRF2 full‐length structures have not been described, although a complete structural model of the CRL complex can be assembled from its different crystallized subunits (Figure 2A).(36,58) Nevertheless, KEAP1‐ Kelch domain complexed with NRF2 peptides containing the ETGE or DLG motifs have been re…”
BackgroundStructure of the BTB Domain of Keap1 and Its Interaction with the Triterpenoid Antagonist CDDO
Cleasby, A., Yon, J. R., Day, P. J., Richardson, C. J., Tickle, I. J., Williams, P. A., Callahan, J. F., Carr, R. A. E., Concha, N. O., Kerns, J. K., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0098896 · Cited by 263 · see citing works
“Further experimental evidence is clearly required to distinguish between these and other possibilities, and a more complete understanding of the effects of Cys 151 perturbation might benefit from structural information for a construct containing at least the first ,50 residues of the BACK domain (the ‘‘3-box’’ motif),…”
BackgroundMethodInfluentialNrf2: a dark horse in Alzheimer's disease treatment
Osama, A., Zhang, J., Yao, J., Yao, X., & Fang, J. (2020) · Ageing Research Reviews · doi:10.1016/j.arr.2020.101206 · Cited by 251 · see citing works
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Mutations in KLHL40 Are a Frequent Cause of Severe Autosomal-Recessive Nemaline Myopathy
Ravenscroft, G., Miyatake, S., Lehtokari, V., Todd, E. J., Vornanen, P., Yau, K. S., Hayashi, Y. K., Miyake, N., Tsurusaki, Y., Doi, H., et al. (2013) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2013.05.004 · Cited by 226 · see citing works
LZTR1 is a regulator of RAS ubiquitination and signaling
Bigenzahn, J. W., Collu, G. M., Kartnig, F., Pieraks, M., Vladimer, G. I., Heinz, L. X., Sedlyarov, V., Schischlik, F., Fauster, A., Rebsamen, M., et al. (2018) · Science · doi:10.1126/science.aap8210 · Cited by 224 · see citing works
Structural basis of NPR1 in activating plant immunity
Kumar, S., Zavaliev, R., Wu, Q., Zhou, Y., Cheng, J., Dillard, L. B., Powers, J. J., Withers, J., Zhao, J., Guan, Z., et al. (2022) · Nature · doi:10.1038/s41586-022-04699-w · Cited by 201 · see citing works
Redox toxicology of environmental chemicals causing oxidative stress
Zheng, F., Gonçalves, F. M., Abiko, Y., Li, H., Kumagai, Y., & Aschner, M. (2020) · Redox Biology · doi:10.1016/j.redox.2020.101475 · Cited by 190 · see citing works
Dysregulation of Nrf2 in Hepatocellular Carcinoma: Role in Cancer Progression and Chemoresistance
Raghunath, A., Sundarraj, K., Arfuso, F., Sethi, G., & Perumal, E. (2018) · Cancers · doi:10.3390/cancers10120481 · Cited by 184 · see citing works
“The IVR domain (aka BACK domain) mediates the interaction of Cul3 with Keap1 through the 3-box bihelical motif in the proximal part in the N-terminal end called the ‘3-box’ [72].”
BackgroundE3 ligase ligand chemistries: from building blocks to protein degraders
Sosič, I., Bricelj, A., & Steinebach, C. (2022) · Chemical Society Reviews · doi:10.1039/d2cs00148a · Cited by 173 · see citing works
Keap Calm, and Carry on Covalently
Wilson, A. J., Kerns, J. K., Callahan, J. F., & Moody, C. J. (2013) · Journal of Medicinal Chemistry · doi:10.1021/jm400224q · Cited by 171 · see citing works
Nrf2 as regulator of innate immunity: A molecular Swiss army knife!
Battino, M. A., Giampieri, F., Pistollato, F., Sureda, A., de Oliveira, M. R., Pittalà, V., Fallarino, F., Nabavi, S. F., Atanasov, A. G., & Nabavi, S. M. (2017) · Biotechnology Advances · doi:10.1016/j.biotechadv.2017.12.012 · Cited by 168 · see citing works
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Organoselenium compounds as mimics of selenoproteins and thiol modifier agents
Barbosa, N. V., Nogueira, C. W., Nogara, P. A., Bem, A. F. D., Aschner, M., & Rocha, J. B. T. (2017) · Metallomics · doi:10.1039/c7mt00083a · Cited by 167 · see citing works
Potential Applications of NRF2 Modulators in Cancer Therapy
Panieri, E., Djordjević, A. B., Telkoparan‐Akillilar, P., Cevik, D., Kouretas, D., Veskoukis, A. S., Skaperda, Z., Tsatsakis, A. M., Wallace, D., Süzen, S., et al. (2020) · Antioxidants · doi:10.3390/antiox9030193 · Cited by 165 · see citing works
“All the members of this family assemble with Cullin-RING ligases that catalyze general protein ubiquitylation [39].”
BackgroundKelch proteins: emerging roles in skeletal muscle development and diseases
Gupta, V., & Beggs, A. H. (2014) · Skeletal Muscle · doi:10.1186/2044-5040-4-11 · Cited by 154 · see citing works
“In humans, dominant CUL3 mutations are associated with pseudohypoaldosteronism type II, a genetic disorder causing hypertension, hyperkalemia, and metabolic acidosis [92].”
BackgroundInfluentialCrystal Structure of the Cul2-Rbx1-EloBC-VHL Ubiquitin Ligase Complex
Cardote, T. A. F., Gadd, M. S., & Ciulli, A. (2017) · Structure · doi:10.1016/j.str.2017.04.009 · Cited by 148 · see citing works
“The CRL2VHL Complex Is Dynamic and Flexible (A) Crystal structures of the full NTD of Cul1 (PDB: 1U6G), Cul2 (PDB: 5N4W), Cul3 (PDB: 4HXI), Cul4A (PDB: 4A0K), Cul4B (PDB: 4A64), and Cul5 (PDB: 4JGH), illustrating the existence of hinge points in the linkers between Cullin repeats.”
BackgroundBardoxolone conjugation enables targeted protein degradation of BRD4
Tong, B., Luo, M., Xie, Y., Spradlin, J. N., Tallarico, J. A., McKenna, J. M., Schirle, M., Maimone, T. J., & Nomura, D. K. (2020) · Scientific Reports · doi:10.1038/s41598-020-72491-9 · Cited by 149 · see citing works
COPII‐mediated trafficking at the ER/ERGIC interface
Peotter, J. L., Kasberg, W., Pustova, I., & Audhya, A. (2019) · Traffic · doi:10.1111/tra.12654 · Cited by 143 · see citing works
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“For BTB-BACK containing proteins SPOP (speckle-type POZ protein), however, the C-terminal BACK-like domain together with the adjacent BTB domian are essential for interaction with CUL3 (Canning et al., 2013).”
BackgroundHyperkalemic hypertension–associated cullin 3 promotes WNK signaling by degrading KLHL3
McCormick, J. A., Yang, C., Zhang, C., Davidge, B., Blankenstein, K. I., Terker, A. S., Yarbrough, B., Meermeier, N. P., Park, H. J., McCully, B. H., et al. (2014) · Journal of Clinical Investigation · doi:10.1172/jci76126 · Cited by 139 · see citing works
Stabilizing mutations of KLHL24 ubiquitin ligase cause loss of keratin 14 and human skin fragility
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Absolute Amounts and Status of the Nrf2-Keap1-Cul3 Complex within Cells
Iso, T., Suzuki, T., Baird, L., & Yamamoto, M. P. (2016) · Molecular and Cellular Biology · doi:10.1128/mcb.00389-16 · Cited by 130 · see citing works
“shows that two Cul3 proteins bind to the Keap1 homodimer (19).”
BackgroundMethodInfluentialKLHL40 deficiency destabilizes thin filament proteins and promotes nemaline myopathy
Garg, A., O’Rourke, J., Long, C., Doering, J., Ravenscroft, G., Bezprozvannaya, S., Nelson, B. R., Beetz, N., Li, L., Chen, S., et al. (2014) · Journal of Clinical Investigation · doi:10.1172/jci74994 · Cited by 127 · see citing works
Methylmercury's chemistry: From the environment to the mammalian brain
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Lymphoma Driver Mutations in the Pathogenic Evolution of an Iconic Human Autoantibody
Singh, M., Jackson, K., Wang, J. J., Schofield, P., Field, M. A., Koppstein, D., Peters, T. J., Burnett, D. L., Rizzetto, S., Névoltris, D., et al. (2020) · Cell · doi:10.1016/j.cell.2020.01.029 · Cited by 120 · see citing works
The role of natural products in revealing NRF2 function
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Cullin-RING E3 Ubiquitin Ligases: Bridges to Destruction
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Structural complexity in the KCTD family of Cullin3-dependent E3 ubiquitin ligases
Pinkas, D. M., Sanvitale, C., Bufton, J. C., Sorrell, F. J., Solcan, N., Chalk, R., Doutch, J., & Bullock, A. N. (2017) · Biochemical Journal · doi:10.1042/bcj20170527 · Cited by 94 · see citing works
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“Besides substrate binding, CRL3 dimerization positions substrates between two E2 binding sites, possibly affecting efficiency and processivity of ubiquitin transfer (Canning et al., 2013).”
BackgroundRavenscroft, G., Laing, N. G., & Bönnemann, C. G. (2014) · Brain · doi:10.1093/brain/awu368 · Cited by 89 · see citing works
“bind cullin 3 to form E3 ubiquitin ligases (Sambuughin et al., 2012; Canning et al., 2013), has been shown to cause nemaline myopathies [KBTBD13 (Sambuughin et al.”
BackgroundInsights into Cullin-RING E3 Ubiquitin Ligase Recruitment: Structure of the VHL-EloBC-Cul2 Complex
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Kelch-like proteins: Physiological functions and relationships with diseases
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Clinical and molecular heterogeneity of pineal parenchymal tumors: a consensus study
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Keap1-Nrf2 pathway: a key mechanism in the occurrence and development of cancer
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The ubiquitin–proteasome system as a transcriptional regulator of plant immunity
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Non-electrophilic modulators of the canonical Keap1/Nrf2 pathway
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Self-citationCullin 3-Based Ubiquitin Ligases as Master Regulators of Mammalian Cell Differentiation
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“dimerizing, BTB proteins are able to recruit two CUL3 subunits into CRL3 complexes [9, 19, 20].”
BackgroundCrystal Structure of KLHL3 in Complex with Cullin3
Ji, A. X., & Privé, G. G. (2013) · PLoS ONE · doi:10.1371/journal.pone.0060445 · Cited by 76 · see citing works
Structural Insights into KCTD Protein Assembly and Cullin3 Recognition
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Medulloblastoma genomics in the modern molecular era
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“KBTBD4 is a poorly characterized member of the Kelch–BTB–BACK family, which consists of proteins involved in the ubiquitin–proteasome pathway (7).”
BackgroundLee, J. C., Mazor, T., Lao, R., Wan, E., Diallo, A. B., Hill, N. S., Thangaraj, N., Wendelsdorf, K., Samuel, D., Kline, C. N., et al. (2019) · Acta Neuropathologica · doi:10.1007/s00401-019-01990-5 · Cited by 71 · see citing works
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Cullin3-KLHL15 ubiquitin ligase mediates CtIP protein turnover to fine-tune DNA-end resection
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“1c), which is the closest ortholog of KLHL15 (refs 18,21).”
Zhang, Y., Shi, Z., Zhou, Y., Xiao, Q., Wang, H., & Peng, Y. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b01865 · Cited by 67 · see citing works
Pallesen, J. S., Narayanan, D., Tran, K. T., Solbak, S. M. Ø., Marseglia, G., Sørensen, L. M. E., Høj, L. J., Munafò, F., Carmona, R. M., Garcia, A. D., et al. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c02094 · Cited by 66 · see citing works
Cullin 3 as a novel target in diverse pathologies
Andérica‐Romero, A. C., González-Herrera, I. G., Santamarı́a, A., & Pedraza‐Chaverrí, J. (2013) · Redox Biology · doi:10.1016/j.redox.2013.07.003 · Cited by 63 · see citing works
“Received 24 June 2013 Received in revised form 28 June 2013 Accepted 9 July 2013”
BackgroundBTB domains: A structural view of evolution, multimerization, and protein–protein interactions
Bonchuk, A. N., Balagurov, K., & Georgiev, P. G. (2022) · BioEssays · doi:10.1002/bies.202200179 · Cited by 64 · see citing works
“found to interact with the Cullin3 protein.[16,34] The available structures suggest that Cullins interact with both KLHL and Skp1/Elongin C BTB-proteins via two contact surfaces (Figure 4A).”
BackgroundMethodInfluentialStructural and mechanistic insights into the Keap1-Nrf2 system as a route to drug discovery
Madden, S. K., & Itzhaki, L. S. (2020) · Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics · doi:10.1016/j.bbapap.2020.140405 · Cited by 60 · see citing works
UM171 glues asymmetric CRL3–HDAC1/2 assembly to degrade CoREST corepressors
Yeo, M. J. R., Zhang, O., Xie, X., Nam, E., Payne, N. C., Gosavi, P. M., Kwok, H. S., Iram, I., Lee, C., Li, J., et al. (2025) · Nature · doi:10.1038/s41586-024-08532-4 · Cited by 58 · see citing works
Protein Degradation Systems as Antimalarial Therapeutic Targets
Ng, C. L., Fidock, D. A., & Bogyo, M. S. (2017) · Trends in Parasitology · doi:10.1016/j.pt.2017.05.009 · Cited by 58 · see citing works
Li, J., Su, X., Wang, Y., Yang, W. C., Pan, Y., Su, C., & Zhang, X. (2017) · Genes & Genomics · doi:10.1007/s13258-017-0604-x · Cited by 57 · see citing works
“The BACK constitutes a novel conserved domain, which is an adaptor and/or a chaperone in the ubiquitin–proteasome proteindegradation pathway and functions during the assembly of Cullin3-based E3 ligase complexes (Canning et al. 2013; Friedman et al. 2009).”
BackgroundWang, L., Cai, X., Shi, M., Xue, L., Kuang, S., Xu, R., Qi, W., Li, Y., Ma, X., Zhang, R., et al. (2020) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2020.112385 · Cited by 57 · see citing works
Hundley, F. V., Sanvisens, N., Marin, H. C., Carr, K. L., Tian, R., & Toczyski, D. P. (2021) · Molecular Cell · doi:10.1016/j.molcel.2021.01.014 · Cited by 55 · see citing works
“For CUL3 substrate receptors, which interact with CUL3 via BTB domains and in particular the 3-box motif within the BTB, sgRNAs targeting the BTB domain were designed (Canning et al., 2013).”
BackgroundWong, M. H. L., Bryan, H. K., Copple, I. M., Jenkins, R. E., Chiu, P. H., Bibby, J., Berry, N. G., Kitteringham, N. R., Goldring, C. E., O’Neill, P. M., et al. (2016) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5b01292 · Cited by 56 · see citing works
Nrf2 and Notch Signaling in Lung Cancer: Near the Crossroad
Sparaneo, A., Fabrizio, F. P., & Muscarella, L. A. (2016) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2016/7316492 · Cited by 54 · see citing works
Cullin 3 Recognition Is Not a Universal Property among KCTD Proteins
Smaldone, G., Pirone, L., Balasco, N., Gaetano, S. D., Pedone, E. M., & Vitagliano, L. (2015) · PLoS ONE · doi:10.1371/journal.pone.0126808 · Cited by 52 · see citing works
Hu, Y., Wang, Y., Wang, F., Dong, Y., Jiang, W., Wang, Y., Zhong, X., & Ma, L. (2020) · Cellular and Molecular Immunology · doi:10.1038/s41423-020-0411-1 · Cited by 52 · see citing works
Cullin-RING ubiquitin ligases in salicylic acid-mediated plant immune signaling
Furniss, J. J., & Spoel, S. H. (2015) · Frontiers in Plant Science · doi:10.3389/fpls.2015.00154 · Cited by 51 · see citing works
Coppée, R., Jeffares, D. C., Miteva, M. A., Sabbagh, A., & Clain, J. (2019) · Scientific Reports · doi:10.1038/s41598-019-47034-6 · Cited by 50 · see citing works
Proximity labeling reveals novel interactomes in live Drosophila tissue
Mannix, K. M., Starble, R. M., Kaufman, R. S., & Cooley, L. (2019) · Development · doi:10.1242/dev.176644 · Cited by 49 · see citing works
“APEX fused to the Kelch N-terminus, which is the site of Kelch homodimerization through its BTB domain (Errington et al., 2012; Canning et al., 2013; Ji and Prive, 2013) labeled distinct proteins compared to APEX::KREP, which contains just the substrate-binding domain of Kelch.”
BackgroundRevisiting the NaCl cotransporter regulation by with-no-lysine kinases
Bazúa‐Valenti, S., & Gamba, G. (2015) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00065.2015 · Cited by 46 · see citing works
Panieri, E., & Saso, L. (2021) · Antioxidants and Redox Signaling · doi:10.1089/ars.2020.8146 · Cited by 46 · see citing works
GCL and CUL3 Control the Switch between Cell Lineages by Mediating Localized Degradation of an RTK
Pae, J., Cinalli, R. M., Marzio, A., Pagano, M., & Lehmann, R. (2017) · Developmental Cell · doi:10.1016/j.devcel.2017.06.022 · Cited by 47 · see citing works
“S1A) (Canning et al., 2013).”
McMahon, M. J., Swift, S., & Hayes, J. D. (2018) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2018.09.033 · Cited by 46 · see citing works
MYC induces CDK4/6 inhibitors resistance by promoting pRB1 degradation
Ma, J., Li, L., Ma, B., Liu, T., Wang, Z., Ye, Q., Peng, Y., Wang, B., Chen, Y., Xu, S., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-45796-w · Cited by 44 · see citing works
The Keap1–Nrf2 protein–protein interaction: A suitable target for small molecules
Schmoll, D., Engel, C. K., & Glombik, H. (2017) · Drug Discovery Today Technologies · doi:10.1016/j.ddtec.2017.10.001 · Cited by 43 · see citing works
Quality control of protein complex composition
Padovani, C., Jevtić, P., & Rapé, M. (2022) · Molecular Cell · doi:10.1016/j.molcel.2022.02.029 · Cited by 43 · see citing works
Chen, Z., Ioris, R. M., Richardson, S., Van Ess, A. N., Vendrell, I., Kessler, B. M., Buffa, F. M., Busino, L., Clifford, S. C., Bullock, A. N., et al. (2022) · Cell Death & Differentiation · doi:10.1038/s41418-022-00983-4 · Cited by 41 · see citing works
Self-citationIslam, S. S., Qassem, K., Islam, S., Parag, R. R., Rahman, M. Z., Farhat, W. A., Yeger, H., Aboussekhra, A., Karakas, B., & Noman, A. S. M. (2022) · Cell Death and Disease · doi:10.1038/s41419-022-05126-8 · Cited by 41 · see citing works
“1766A > G) of Keap1, which are responsible for the ubiquitination and binding of Nrf2 [46, 47].”
BackgroundDesign and characterization of a heterobifunctional degrader of KEAP1
Chen, H., Nguyen, N. H., Magtoto, C. M., Cobbold, S. A., Bidgood, G. M., Guzman, L. G. M., Richardson, L. W., Corbin, J. E., Au, A. E., Lechtenberg, B. C., et al. (2022) · Redox Biology · doi:10.1016/j.redox.2022.102552 · Cited by 41 · see citing works
“KEAP1-kelch molecules in the homodimeric degradative E3 complex [8, 9].”
BackgroundDeficiency in Kelch protein Klhl31 causes congenital myopathy in mice
Papizan, J. B., Garry, G. A., Brezprozvannaya, S., McAnally, J., Bassel‐Duby, R., Liu, N., & Olson, E. N. (2017) · Journal of Clinical Investigation · doi:10.1172/jci93445 · Cited by 41 · see citing works
- Authors
- Canning, P., Cooper, C. D. O., Krojer, T., Murray, J. W., Pike, A. C. W., Chaikuad, A., Keates, T., Thangaratnarajah, C., Hojzan, V., Marsden, B. D., Gileadi, O., Knapp, S., von Delft, F., & Bullock, A. N.
- Affiliations
- University of Oxford (GB)
- Corresponding author
- Bullock, Alex N.
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2013-03
- Volume
- 288
- Issue
- 11
- Pages
- 7803-7814
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3597819
- OpenAlex
- W2029330932
- Cited by
- 284
- References
- 71
- Citations by year
- 2026: 16 · 2025: 22 · 2024: 22 · 2023: 18 · 2022: 25 · 2021: 28 · 2020: 32 · 2019: 22 · 2018: 13 · 2017: 23 · 2016: 15 · 2015: 20 · 2014: 15 · 2013: 13
- FWCI
- 9.41
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- University of Huddersfield Repository (University of Huddersfield) (acceptedVersion)
- DORA PSI (Paul Scherrer Institute) (submittedVersion, cc-by)
- Funders
- Eli Lilly and Company
- Pfizer (1097737)
- GlaxoSmithKline
- Genome Canada (1097737)
- Wellcome Trust (092809, 092809/Z/10/Z, 1097737, 092809/Z/10)
- Diamond Light Source (1097737)
- Ontario Ministry of Economic Development and Innovation (092809/Z/10/Z, 1097737)
- Ministero dello Sviluppo Economico
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Keywords
- CUL3, cullin-RING ligases, protein assembly, Kelch domain, N-terminal extension, Keap1, E3 ubiquitin ligase inhibitors, crystal structure
- MeSH terms
- Binding Sites, Calorimetry, Carrier Proteins, Humans, Models, Molecular, Molecular Conformation, Phylogeny, Protein Binding, Protein Conformation, Substrate Specificity, Protein Structure, Secondary, Protein Structure, Tertiary, Crystallography, X-Ray, Dimerization, Ubiquitin, Protein Interaction Mapping, Ubiquitin-Protein Ligases, Cullin Proteins, Proteasome Endopeptidase Complex
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