E3 ubiquitin ligase components | Enzymes | IUPHAR/BPS Guide to PHARMACOLOGY

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E3 ubiquitin ligase components

E3 ubiquitin ligase components C

Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).

Overview

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Ubiquitination (a.k.a. ubiquitylation) is a protein post-translational modification that typically requires the sequential action of three enzymes: E1 (ubiquitin-activating enzymes), E2 (ubiquitin-conjugating enzymes), and E3 (ubiquitin ligases) [25]. Ubiquitination of proteins can target them for proteasomal degradation, or modulate cellular processes including cell cycle progression, transcriptional regulation, DNA repair and signal transduction.
E3 ubiquitin ligases, of which there are >600 in humans, are a family of highly heterogeneous proteins and protein complexes that recruit ubiquitin-loaded E2 enzymes to mediate transfer of the ubiquitin molecule from the E2 to protein substrates. Target substrate specificity is determined by a substrate recognition subunit within the E3 complex.
E3 ligases are being exploited as pharmacological targets to facilitate targeted protein degradation (TPD), as an alternative to small molecule inhibitors [2], through the development of proteolysis targeting chimeras (PROTACs) and molecular glues.

Enzymes

3346

Cbl proto-oncogene B Show summary »« Hide summary

Target Id

3234

Nomenclature

Cbl proto-oncogene B

Previous and unofficial names

Casitas B-lineage lymphoma b | casitas B-lineage lymphoma proto-oncogene-b

Genes

CBLB (Hs), Cblb (Mm), Cblb (Rn)

Ensembl ID

ENSG00000114423 (Hs), ENSMUSG00000022637 (Mm), ENSRNOG00000001982 (Rn)

UniProtKB AC

Q13191 (Hs), Q3TTA7 (Mm), Q8K4S7 (Rn)

Inhibitors

NX-1607 pIC₅₀ 7.0 – 7.7 [30]

Comment

Cbl-b is an E3 ubiquitin ligase that is an active therapeutic drug target [1,13,30], based on evidence that it has oncogenic actions in some cancers. Inhibiting Cbl-b has been shown to induce antitumour immunity [9].

cereblon C Show summary »« Hide summary More detailed page go icon to follow link

Target Id

3086

Nomenclature

cereblon

Previous and unofficial names

mental retardation, non-syndromic, autosomal recessive, 2A | MRT2A

Genes

CRBN (Hs), Crbn (Mm), Crbn (Rn)

Ensembl ID

ENSG00000113851 (Hs), ENSMUSG00000005362 (Mm), ENSRNOG00000006534 (Rn)

UniProtKB AC

Q96SW2 (Hs), Q8C7D2 (Mm), Q56AP7 (Rn)

Ligands

thalidomide (Binding) pK_d 8.1 [12]

Comment

Cereblon is the substrate-recognition module of the cullin-RING type E3 ubiquitin ligase CRL4

DDB1 and CUL4 associated factor 1 Show summary »« Hide summary

Target Id

3244

Nomenclature

DDB1 and CUL4 associated factor 1

Previous and unofficial names

VPRBP | Vpr (HIV-1) binding protein

Genes

DCAF1 (Hs), Dcaf1 (Mm), Dcaf1 (Rn)

Ensembl ID

ENSG00000145041 (Hs), ENSMUSG00000040325 (Mm), ENSRNOG00000013841 (Rn)

UniProtKB AC

Q9Y4B6 (Hs), Q3UXD5 (Mm)

Inhibitors

compound 13 [PMID: 37465299] (Binding) pK_d 7.5 [34]

OICR-8268 (Binding) pK_d 7.4 [22]

YT47R (Binding) [31]

Comment

The DCAF1 protein is a substrate binding component of the Cullin4-RING E3 ubiquitin ligase complex. Its exploitation for targeted protein degradation is being evaluated for therapeutic potential [22,31,34].

F-box protein 3 Show summary »« Hide summary

Target Id

3233

Nomenclature

F-box protein 3

Genes

FBXO3 (Hs), Fbxo3 (Mm), Fbxo3 (Rn)

Ensembl ID

ENSMUSG00000027180 (Mm), ENSRNOG00000009549 (Rn), ENSG00000110429

UniProtKB AC

Q9UK99 (Hs), Q9DC63 (Mm), D4ABP9 (Rn)

Inhibitors

BC-1215 pIC₅₀ 5.6 [6]

Comment

F-box protein 3 is one of the components of the SCF (Skp, Cullin, F-box containing) complex, which is a multi-protein E3 ubiquitin ligase complex that catalyses the ubiquitination of proteins to direct them for proteasomal degradation. Structurally F-box protein 3 contains an F-box domain and an ApaG motif in its C-terminal domain. It is involved in pathways that regulate pro-inflammatory cytokine release, and is a molecular target for anti-inflammatory drug development.

kelch domain containing 2 Show summary »« Hide summary

Target Id

3262

Nomenclature

kelch domain containing 2

Genes

KLHDC2 (Hs), Klhdc2 (Mm), Klhdc2 (Rn)

Ensembl ID

ENSMUSG00000020978 (Mm), ENSRNOG00000004474 (Rn), ENSG00000165516

UniProtKB AC

Q9Y2U9 (Hs), E9QKN6 (Mm), KLDC2_RAT (Rn)

Endogenous substrates

selenoprotein K (SELENOK)

Ligands

KYH1872 (Binding) pK_d >8.7 [17]

Comment

KLHDC2 is a substrate-recognition component of a Cul2-RING (CRL2) E3 ubiquitin-protein ligase complex that is part of the C-end degron protein homeostasis pathway [18,23,29]. It has been identified as a suitable and tractable ubiquitin E3 ligase for PROTAC design and development [17].

kelch like family member 12 Show summary »« Hide summary

Target Id

3346

Nomenclature

kelch like family member 12

Genes

KLHL12 (Hs), Klhl12 (Mm), Klhl12 (Rn)

Ensembl ID

ENSG00000117153 (Hs), ENSMUSG00000026455 (Mm), ENSRNOG00000004193 (Rn)

UniProtKB AC

Q53G59 (Hs), Q8BZM0 (Mm), Q8R2H4 (Rn)

Ligands

compound 7k [PMID: 41906311] (Binding) pK_d 6.3 [36]

Comment

The KLHL12 protein has been identified as a substrate adaptor of the Cullin-3 ubiquitin ligase complex (or E3 ligase) that is involved in promoting substrate-specific ubiquitylation leading to proteasomal degradation. It is more highly expressed in cancer cells compared to normal tissues. KLHL12-binding ligands may be of use in the design of tumour-selective PROTAC degraders [36].

MDM2 proto-oncogene Show summary »« Hide summary More detailed page go icon to follow link

Target Id

3136

Nomenclature

MDM2 proto-oncogene

Previous and unofficial names

transformed mouse 3T3 cell double minute 2 | E3 ubiquitin-protein ligase Mdm2 | p53-binding protein Mdm2 | RING-type E3 ubiquitin transferase Mdm2

Genes

MDM2 (Hs), Mdm2 (Mm), Mdm2 (Rn)

Ensembl ID

ENSG00000135679 (Hs), ENSMUSG00000020184 (Mm), ENSRNOG00000006304 (Rn), ENSMUSG00000020184

UniProtKB AC

Q00987 (Hs), P23804 (Mm)

EC number

2.3.2.27

Comment

MDM2 is a nuclear E3 ubiquitin-protein ligase that can promote oncogenic transformation via p53 modulation.

S-phase kinase associated protein 2 Show summary »« Hide summary

Target Id

3235

Nomenclature

S-phase kinase associated protein 2

Previous and unofficial names

FBL1 | FBXL1

Genes

SKP2 (Hs), Skp2 (Mm), Skp2 (Rn)

Ensembl ID

ENSG00000145604 (Hs), ENSMUSG00000054115 (Mm), ENSRNOG00000059059 (Rn)

UniProtKB AC

Q13309 (Hs), Q99J53 (Mm)

Inhibitors

compound 14i [PMID: 37204466] pIC₅₀ 8.6 [38]

Comment

Skp2 is a F-box domain-containing protein that acts as a substrate recognition component of cullin-RING E3 ubiquitin ligase complexes. It binds regulatory subunits of cyclin-dependent kinases (CKS1A and CKS1B) that modulate the biological function of cyclin dependent kinases catalytic activity, and are thus involved in regulating G1/S transition in the cell cycle. Skp2 is an oncology drug target.

STIP1 homology and U-box containing protein 1 Show summary »« Hide summary More detailed page go icon to follow link

Target Id

3202

Nomenclature

STIP1 homology and U-box containing protein 1

Previous and unofficial names

E3 ubiquitin-protein ligase CHIP | carboxy terminus of the Hsp70-interacting protein (CHIP) | UBOX1 | NY-CO-7

Genes

STUB1 (Hs), Stub1 (Mm), Stub1 (Rn)

Ensembl ID

ENSG00000103266 (Hs), ENSMUSG00000039615 (Mm), ENSRNOG00000019798 (Rn)

UniProtKB AC

Q9UNE7 (Hs), Q9WUD1 (Mm)

EC number

2.3.2.27

Inhibitors

peptide 22d (Binding) pK_d 6.3 [27]

Comment

STUB1 is an E3 ubiquitin ligase/cochaperone that is involved in the protein refolding cycle. It regulates a variety of physiological functions and it has been associated with neurodegeneration, aging and malignancy [4,14,19]. STUB1 is a potential cancer therapeutic target [27].

ubiquitin protein ligase E3 component n-recognin 2 Show summary »« Hide summary

Target Id

3354

Nomenclature

ubiquitin protein ligase E3 component n-recognin 2

Previous and unofficial names

N-recognin-2

Genes

UBR2 (Hs), Ubr2 (Mm), Ubr2 (Rn)

Ensembl ID

ENSG00000024048 (Hs), ENSMUSG00000023977 (Mm), ENSRNOG00000015813 (Rn)

UniProtKB AC

Q8IWV8 (Hs), Q6WKZ8 (Mm)

EC number

2.3.2.27

Inhibitors

AF23 (Binding) pK_d 7.7 [11]

Comment

The UBR2 protein is a component of E3 ubiquitin ligase complex that is a participant in the Arg/N-degron (N-end rule) pathway with a role in the ER stress response in mammalian cells [10,16,20,28,32-33]. UBR2 binding to substrate proteins bearing specific N-terminal residues (known as N-degrons; specifically methylated N-degrons and those with Arg, Lys and His N-terminal residues) leads to their ubiquitination and subsequent degradation [24,26]. UBR2 has been established as a potential molecular target to treat cancer- and diabetes-associated cachexia, as it is associated with targeting muscle proteins (e.g., myosin heavy chains IIb and IIx) for proteasomal degradation [8]. UBR2 is also involved in NLRP1B inflammasome activation by pathogens and other DAMPS [35,37].

von Hippel-Lindau tumor suppressor Show summary »« Hide summary

Target Id

3204

Nomenclature

von Hippel-Lindau tumor suppressor

Genes

VHL (Hs)

Ensembl ID

ENSG00000134086 (Hs)

UniProtKB AC

P40337 (Hs)

Ligands

MS8815 (Binding) pK_d ~6.7 [7]

Comment

VHL is a component of the ubiquitination complex, and it recruits the E3 ubiquitin protein ligase, to mediate degdadation of hypoxia-inducible-factor (HIF). This role in protein degradation is exploited for the design of PROTAC molecules that induce the selective degradation of proteins, other than HIF, that are involved in human diseases (most commonly cancers, but also autoimmune conditions).

zinc finger and BTB domain containing 25 Show summary »« Hide summary

Target Id	3254
Nomenclature	zinc finger and BTB domain containing 25
Previous and unofficial names	KUP \| Zfp50 \| ZNF46
Genes	ZBTB25 (Hs), Zbtb25 (Mm), Zbtb25 (Rn)
Ensembl ID	ENSG00000089775 (Hs), ENSMUSG00000056459 (Mm), ENSRNOG00000006441 (Rn)
UniProtKB AC	P24278 (Hs), Q6P754 (Rn)
Comment	ZBTB25 has established transcription repressor and epigenetic regulator functions [3,5,15]. It has more recently been identified as demonstrating E3 ligase activity that is directly involved in ubiquitination of SARS-CoV-2 Mpro (main protease) leading to its degradation via the ubiquitin proteasome system (UPS) in host cells [21]. The consequence of this latter mechanism is proposed to limit coronavirus infection and viral propagation.

References

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1. Augustin RC, Bao R, Luke JJ. (2023) Targeting Cbl-b in cancer immunotherapy. J Immunother Cancer, 11 (2). [PMID:36750253]

2. Belcher BP, Ward CC, Nomura DK. (2023) Ligandability of E3 Ligases for Targeted Protein Degradation Applications. Biochemistry, 62 (3): 588-600. [PMID:34473924]

3. Benita Y, Cao Z, Giallourakis C, Li C, Gardet A, Xavier RJ. (2010) Gene enrichment profiles reveal T-cell development, differentiation, and lineage-specific transcription factors including ZBTB25 as a novel NF-AT repressor. Blood, 115 (26): 5376-84. [PMID:20410506]

4. Cao Z, Li G, Shao Q, Yang G, Zheng L, Zhang T, Zhao Y. (2016) CHIP: A new modulator of human malignant disorders. Oncotarget, 7 (20): 29864-74. [PMID:27007160]

5. Chardin P, Courtois G, Mattei MG, Gisselbrecht S. (1991) The KUP gene, located on human chromosome 14, encodes a protein with two distant zinc fingers. Nucleic Acids Res, 19 (7): 1431-6. [PMID:2027750]

6. Chen B, Mallampalli R. (2018) Compositions and methods for treating respiratory injury or disease. Patent number: US20180071232A. Assignee: University of Pittsburgh , US Department of Veterans Affairs VA. Priority date: 17/11/2017. Publication date: 15/03/2018.

7. Dale B, Anderson C, Park KS, Kaniskan HÜ, Ma A, Shen Y, Zhang C, Xie L, Chen X, Yu X et al.. (2022) Targeting Triple-Negative Breast Cancer by a Novel Proteolysis Targeting Chimera Degrader of Enhancer of Zeste Homolog 2. ACS Pharmacol Transl Sci, 5 (7): 491-507. [PMID:35837138]

8. Gao S, Zhang G, Zhang Z, Zhu JZ, Li L, Zhou Y, Rodney Jr GG, Abo-Zahrah RS, Anderson L, Garcia JM et al.. (2022) UBR2 targets myosin heavy chain IIb and IIx for degradation: Molecular mechanism essential for cancer-induced muscle wasting. Proc Natl Acad Sci U S A, 119 (43): e2200215119. [PMID:36252004]

9. Han S, Liu ZQ, Chung DC, Paul MS, Garcia-Batres CR, Sayad A, Elford AR, Gold MJ, Grimshaw N, Ohashi PS. (2022) Overproduction of IFNγ by Cbl-b-Deficient CD8+ T Cells Provides Resistance against Regulatory T Cells and Induces Potent Antitumor Immunity. Cancer Immunol Res, 10 (4): 437-452. [PMID:35181779]

10. Huang ST, Chen DH, Ren T, Thomas N, Wu J, Sankaran B, Jones R, Taylor S, Chen Y. (2025) An alternative pocket for binding the N-degrons by the UBR1 and UBR2 ubiquitin E3 ligases. Protein Sci, 34 (8): e70248. [PMID:40880185]

11. Huang ST, Faouzi A, Thomas N, Wu J, Pestonjamasp K, Chen DH, Ren T, Kuang Y, Taylor S, Chen Y. (2026) Development of High-Affinity Ligands for Human UBR2. J Med Chem, 69 (10): 11738-11751. [PMID:42102356]

12. Ito T, Ando H, Suzuki T, Ogura T, Hotta K, Imamura Y, Yamaguchi Y, Handa H. (2010) Identification of a primary target of thalidomide teratogenicity. Science, 327 (5971): 1345-50. [PMID:20223979]

13. Jafari D, Mousavi MJ, Keshavarz Shahbaz S, Jafarzadeh L, Tahmasebi S, Spoor J, Esmaeilzadeh A. (2021) E3 ubiquitin ligase Casitas B lineage lymphoma-b and its potential therapeutic implications for immunotherapy. Clin Exp Immunol, 204 (1): 14-31. [PMID:33306199]

14. Joshi V, Amanullah A, Upadhyay A, Mishra R, Kumar A, Mishra A. (2016) A Decade of Boon or Burden: What Has the CHIP Ever Done for Cellular Protein Quality Control Mechanism Implicated in Neurodegeneration and Aging?. Front Mol Neurosci, 9: 93. [PMID:27757073]

15. Karemaker ID, Vermeulen M. (2018) ZBTB2 reads unmethylated CpG island promoters and regulates embryonic stem cell differentiation. EMBO Rep, 19 (4). [PMID:29437775]

16. Kim JG, Shin HC, Seo T, Nawale L, Han G, Kim BY, Kim SJ, Cha-Molstad H. (2021) Signaling Pathways Regulated by UBR Box-Containing E3 Ligases. Int J Mol Sci, 22 (15). [PMID:34361089]

17. Kim Y, Seo P, Jeon E, You I, Hwang K, Kim N, Tse J, Bae J, Choi HS, Hinshaw SM et al.. (2023) Targeted kinase degradation via the KLHDC2 ubiquitin E3 ligase. Cell Chem Biol, 30 (11): 1414-1420.e5. [PMID:37567174]

18. Koren I, Timms RT, Kula T, Xu Q, Li MZ, Elledge SJ. (2018) The Eukaryotic Proteome Is Shaped by E3 Ubiquitin Ligases Targeting C-Terminal Degrons. Cell, 173 (7): 1622-1635.e14. [PMID:29779948]

19. Kumar S, Basu M, Ghosh MK. (2021) Chaperone-assisted E3 ligase CHIP: A double agent in cancer. Genes & Diseases, Epub ahead of print. DOI: 10.1016/j.gendis.2021.08.003

20. Le LTHL, Park S, Lee JH, Kim YK, Lee MJ. (2024) N-recognins UBR1 and UBR2 as central ER stress sensors in mammals. Mol Cells, 47 (1): 100001. [PMID:38376480]

21. Lear TB, Boudreau ÁN, Lockwood KC, Chu E, Camarco DP, Cao Q, Nguyen M, Evankovich JW, Finkel T, Liu Y et al.. (2023) E3 ubiquitin ligase ZBTB25 suppresses beta coronavirus infection through ubiquitination of the main viral protease MPro. J Biol Chem, 299 (12): 105388. [PMID:37890782]

22. Li ASM, Kimani S, Wilson B, Noureldin M, González-Álvarez H, Mamai A, Hoffer L, Guilinger JP, Zhang Y, von Rechenberg M et al.. (2023) Discovery of Nanomolar DCAF1 Small Molecule Ligands. J Med Chem, 66 (7): 5041-5060. [PMID:36948210]

23. Lin HC, Yeh CW, Chen YF, Lee TT, Hsieh PY, Rusnac DV, Lin SY, Elledge SJ, Zheng N, Yen HS. (2018) C-Terminal End-Directed Protein Elimination by CRL2 Ubiquitin Ligases. Mol Cell, 70 (4): 602-613.e3. [PMID:29775578]

24. Matta-Camacho E, Kozlov G, Li FF, Gehring K. (2010) Structural basis of substrate recognition and specificity in the N-end rule pathway. Nat Struct Mol Biol, 17 (10): 1182-7. [PMID:20835242]

25. Morreale FE, Walden H. (2016) Types of Ubiquitin Ligases. Cell, 165 (1): 248-248.e1. [PMID:27015313]

26. Muñoz-Escobar J, Matta-Camacho E, Cho C, Kozlov G, Gehring K. (2017) Bound Waters Mediate Binding of Diverse Substrates to a Ubiquitin Ligase. Structure, 25 (5): 719-729.e3. [PMID:28392261]

27. Ng S, Brueckner AC, Bahmanjah S, Deng Q, Johnston JM, Ge L, Duggal R, Habulihaz B, Barlock B, Ha S et al.. (2022) Discovery and Structure-Based Design of Macrocyclic Peptides Targeting STUB1. J Med Chem, [Epub ahead of print]. [PMID:35853179]

28. Oh JH, Hyun JY, Chen SJ, Varshavsky A. (2020) Five enzymes of the Arg/N-degron pathway form a targeting complex: The concept of superchanneling. Proc Natl Acad Sci U S A, 117 (20): 10778-10788. [PMID:32366662]

29. Rusnac DV, Lin HC, Canzani D, Tien KX, Hinds TR, Tsue AF, Bush MF, Yen HS, Zheng N. (2018) Recognition of the Diglycine C-End Degron by CRL2^KLHDC2 Ubiquitin Ligase. Mol Cell, 72 (5): 813-822.e4. [PMID:30526872]

30. Sands AT, Bence NF, Zapf CW, Cohen F, Wang C, Cummins T, Tanaka H, Shunatona H, Cardozo M, Weiss D et al.. (2020) Substituted benzyl-triazole compounds for cbl-b inhibition, and further uses thereof. Patent number: WO2020264398A1. Assignee: Nurix Therapeutics, Inc.. Priority date: 26/06/2020. Publication date: 30/12/2020.

31. Tao Y, Remillard D, Vinogradova EV, Yokoyama M, Banchenko S, Schwefel D, Melillo B, Schreiber SL, Zhang X, Cravatt BF. (2022) Targeted Protein Degradation by Electrophilic PROTACs that Stereoselectively and Site-Specifically Engage DCAF1. J Am Chem Soc, 144 (40): 18688-18699. [PMID:36170674]

32. Villa E, Paul R, Meynet O, Volturo S, Pinna G, Ricci JE. (2020) The E3 ligase UBR2 regulates cell death under caspase deficiency via Erk/MAPK pathway. Cell Death Dis, 11 (12): 1041. [PMID:33288741]

33. Vu TTM, Mitchell DC, Gygi SP, Varshavsky A. (2020) The Arg/N-degron pathway targets transcription factors and regulates specific genes. Proc Natl Acad Sci U S A, 117 (49): 31094-31104. [PMID:33229537]

34. Vulpetti A, Holzer P, Schmiedeberg N, Imbach-Weese P, Pissot-Soldermann C, Hollingworth GJ, Radimerski T, Thoma CR, Stachyra TM, Wojtynek M et al.. (2023) Discovery of New Binders for DCAF1, an Emerging Ligase Target in the Targeted Protein Degradation Field. ACS Med Chem Lett, 14 (7): 949-954. [PMID:37465299]

35. Wang J, Yang D, Shen X, Wang J, Liu X, Lin J, Zhong J, Zhao Y, Qi Z. (2020) BPTES inhibits anthrax lethal toxin-induced inflammatory response. Int Immunopharmacol, 85: 106664. [PMID:32521490]

36. Waterson AG, Vadukoot A, Jana S, Cui J, Luong K, Rietz TA, Madrigal-Carrillo EA, Lehmann BD, Sensintaffar JL, Zhao B et al.. (2026) Identification of KLHL12 Ligands Using Fragment-Based Methods. J Med Chem, 69 (7): 7709-7731. [PMID:41906311]

37. Xu H, Shi J, Gao H, Liu Y, Yang Z, Shao F, Dong N. (2019) The N-end rule ubiquitin ligase UBR2 mediates NLRP1B inflammasome activation by anthrax lethal toxin. EMBO J, 38 (13): e101996. [PMID:31268597]

38. Zhang K, Hu K, Li Q, Li M, Gao K, Yang K, Zhao B, Shi XJ, Zhang L, Liu HM. (2023) Discovery of Novel 1,3-Diphenylpyrazine Derivatives as Potent S-Phase Kinase-Associated Protein 2 (Skp2) Inhibitors for the Treatment of Cancer. J Med Chem, 66 (11): 7221-7242. [PMID:37204466]

NC-IUPHAR subcommittee and family contributors

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Concise Guide to PHARMACOLOGY citation:

Alexander SPH, Fabbro D, Gibb AJ, Kelly E, Mathie AA, Peach CJ, Veale EL, Armstrong JF, Faccenda E, Harding SD, Southan C, Davies JA et al. (2025) The Concise Guide to PHARMACOLOGY 2025/26: Enzymes. Br J Pharmacol. 182: S307-S403.

E3 ubiquitin ligase components C

Overview

Enzymes

Further reading

References

NC-IUPHAR subcommittee and family contributors

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