Cul4A-RING E3 ubiquitin ligase complex
Definition
Target type: cellularcomponent
A ubiquitin ligase complex in which a cullin from the Cul4A subfamily and a RING domain protein form the catalytic core; substrate specificity is conferred by an adaptor protein. [PMID:15571813, PMID:15688063]
The Cul4A-RING E3 ubiquitin ligase complex is a multi-protein complex that plays a crucial role in regulating various cellular processes, including DNA repair, cell cycle progression, and transcription. It consists of several core components:
**1. Cullin 4A (Cul4A):** This scaffold protein provides the structural foundation for the complex. It acts as a bridge, linking the RING domain protein to the substrate recognition module.
**2. RING Domain Protein:** This component, typically RBX1, provides the catalytic activity of the complex. It binds to the E2 ubiquitin-conjugating enzyme, facilitating the transfer of ubiquitin from E2 to the target substrate.
**3. DDB1:** This protein serves as the adaptor molecule, bridging Cul4A to the substrate recognition module. It has a WD40 domain that binds to the substrate recognition module and interacts with Cul4A.
**4. Substrate Recognition Module:** This is a variable component of the complex, determining the specificity for substrate recognition. Different substrate recognition modules, such as DCAF proteins, bind to specific substrates, targeting them for ubiquitination.
**5. E2 Ubiquitin-Conjugating Enzyme:** This enzyme carries activated ubiquitin and transfers it to the target substrate, facilitated by the RING domain protein.
**Cellular Component:**
The Cul4A-RING E3 ubiquitin ligase complex is localized within the nucleus, where it participates in DNA repair, transcription, and other nuclear processes. It is also found in the cytoplasm, where it plays a role in cell cycle regulation and other cellular functions. The complex is a dynamic entity that can associate with various cellular compartments depending on its specific substrate and function.
**Overall, the Cul4A-RING E3 ubiquitin ligase complex is a versatile and essential cellular machine that orchestrates the ubiquitination of various substrates, controlling their activity, localization, and ultimately, their fate within the cell.**'
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Proteins (3)
| Protein | Definition | Taxonomy |
|---|---|---|
| Protein cereblon | A protein cereblon that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q96SW2] | Homo sapiens (human) |
| DNA damage-binding protein 1 | A DNA damage-binding protein 1 that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q16531] | Homo sapiens (human) |
| Cullin-4A | A cullin-4A that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q13619] | Homo sapiens (human) |
Compounds (30)
| Compound | Definition | Classes | Roles |
|---|---|---|---|
| dimethyl sulfoxide | dimethyl sulfoxide : A 2-carbon sulfoxide in which the sulfur atom has two methyl substituents. Dimethyl Sulfoxide: A highly polar organic liquid, that is used widely as a chemical solvent. Because of its ability to penetrate biological membranes, it is used as a vehicle for topical application of pharmaceuticals. It is also used to protect tissue during CRYOPRESERVATION. Dimethyl sulfoxide shows a range of pharmacological activity including analgesia and anti-inflammation. | sulfoxide; volatile organic compound | alkylating agent; antidote; Escherichia coli metabolite; geroprotector; MRI contrast agent; non-narcotic analgesic; polar aprotic solvent; radical scavenger |
| uracil | 2,4-dihydroxypyrimidine: a urinary biomarker for bipolar disorder | pyrimidine nucleobase; pyrimidone | allergen; Daphnia magna metabolite; Escherichia coli metabolite; human metabolite; mouse metabolite; prodrug; Saccharomyces cerevisiae metabolite |
| rolipram | pyrrolidin-2-ones | antidepressant; EC 3.1.4.* (phosphoric diester hydrolase) inhibitor | |
| thalidomide | 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione : A dicarboximide that is isoindole-1,3(2H)-dione in which the hydrogen attached to the nitrogen is substituted by a 2,6-dioxopiperidin-3-yl group. thalidomide : A racemate comprising equimolar amounts of R- and S-thalidomide. Thalidomide: A piperidinyl isoindole originally introduced as a non-barbiturate hypnotic, but withdrawn from the market due to teratogenic effects. It has been reintroduced and used for a number of immunological and inflammatory disorders. Thalidomide displays immunosuppressive and anti-angiogenic activity. It inhibits release of TUMOR NECROSIS FACTOR-ALPHA from monocytes, and modulates other cytokine action. | phthalimides; piperidones | |
| uridine | uridines | drug metabolite; fundamental metabolite; human metabolite | |
| uridine monophosphate | uridine 5'-monophosphate : A pyrimidine ribonucleoside 5'-monophosphate having uracil as the nucleobase. Uridine Monophosphate: 5'-Uridylic acid. A uracil nucleotide containing one phosphate group esterified to the sugar moiety in the 2', 3' or 5' position. | pyrimidine ribonucleoside 5'-monophosphate; uridine 5'-phosphate | Escherichia coli metabolite; human metabolite; mouse metabolite |
| dimethyl sulfone | sulfone | ||
| hydantoins | Hydantoins: Compounds based on imidazolidine dione. Some derivatives are ANTICONVULSANTS. imidazolidine-2,4-dione : An imidazolidinone with oxo groups at position 2 and 4. | imidazolidine-2,4-dione | |
| succinimide | succinimide : A dicarboximide that is pyrrolidine which is substituted by oxo groups at positions 2 and 5. succinimide: RN given refers to parent cpd | dicarboximide; pyrrolidinone | |
| 1-methyluracil | 1-methyluracil : A pyrimidone that is uracil with a methyl group substituent at position 1. 1-methyluracil: RN given refers to parent cpd; structure | nucleobase analogue; pyrimidone | metabolite |
| 1-methylhydantoin | 1-methylhydantoin: structure in first source | imidazolidine-2,4-dione | bacterial metabolite |
| glutarimide | dicarboximide; piperidones | ||
| 1-aminohydantoin | 1-aminohydantoin: a metabolite of nitrofurantoin | imidazolidine-2,4-dione | |
| n-hydroxysuccinimide | N-hydroxysuccinimide: structure | ||
| 2-(2,6-dioxopiperidin-3-yl)phthalimidine | 2-(2,6-dioxopiperidin-3-yl)phthalimidine: thalidomide analog; structure; RN given refers to cpd without isomeric designation | ||
| peptide elongation factor 2 | (S)-thalidomide : A 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione that has S-configuration at the chiral centre. | 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione | teratogenic agent |
| pomalidomide | 3-aminophthalimidoglutarimide: structure in first source | aromatic amine; dicarboximide; isoindoles; piperidones | angiogenesis inhibitor; antineoplastic agent; immunomodulator |
| lenalidomide | aromatic amine; dicarboximide; isoindoles; piperidones | angiogenesis inhibitor; antineoplastic agent; immunomodulator | |
| 4-pyridin-4-yl-2-sulfanylidene-5,6,7,8-tetrahydro-1H-quinoline-3-carbonitrile | bipyridines | ||
| thiohydantoins | Thiohydantoins: Sulfur analogs of hydantoins with one or both carbonyl groups replaced by thiocarbonyl groups. | ||
| dasatinib | dasatinib (anhydrous) : An aminopyrimidine that is 2-methylpyrimidine which is substituted at position 4 by the primary amino group of 2-amino-1,3-thiazole-5-carboxylic acid and at position 6 by a 4-(2-hydroxyethyl)piperazin-1-yl group, and in which the carboxylic acid group has been formally condensed with 2-chloro-6-methylaniline to afford the corresponding amide. A multi-targeted kinase inhibitor, it is used, particularly as the monohydrate, for the treatment of chronic, accelerated, or myeloid or lymphoid blast phase chronic myeloid leukemia. Note that the name 'dasatinib' is used to refer to the monohydrate (USAN) as well as to anhydrous dasatinib (INN). N-(2-chloro-6-methylphenyl)-2-((6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-yl)amino)-1,3-thiazole-5-carboxamide: a dasatinib prodrug; structure in first source | 1,3-thiazoles; aminopyrimidine; monocarboxylic acid amide; N-(2-hydroxyethyl)piperazine; N-arylpiperazine; organochlorine compound; secondary amino compound; tertiary amino compound | anticoronaviral agent; antineoplastic agent; tyrosine kinase inhibitor |
| furagin | furagin : An imidazolidine-2,4-dione that is hydantoin substituted at position 1 by a [3-(5-nitro-2-furyl)prop-2-en-1-ylidene]amino group (the configuration of the C=C and C=N bonds in the grouping that links the two heterocycles is not specified). A nitrofuran antibiotic with properties similar to nitrofurantoin, furagin is used in the treatment of urinary tract infections. Furagin: Nitrofuran derivative anti-infective agent used for urinary tract infections. | ||
| 2-acetylfuranonaphthoquinone | 2-acetylfuranonaphthoquinone: has antineoplastic activity; structure in first source | ||
| ponatinib | (trifluoromethyl)benzenes; acetylenic compound; benzamides; imidazopyridazine; N-methylpiperazine | antineoplastic agent; tyrosine kinase inhibitor | |
| cc-122 | 3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione: a pleiotropic pathway modifier with antineoplastic activity; structure in first source | ||
| sofosbuvir | sofosbuvir : A nucleotide conjugate that is used in combination with ledipasvir (under the trade name Harvoni) for the treatment of chronic hepatitis C genotype 1 infection. Sofosbuvir: A uridine monophosphate analog inhibitor of HEPATITIS C VIRUS (HCV) polymerase NS5B that is used as an ANTIVIRAL AGENT in the treatment of CHRONIC HEPATITIS C. | isopropyl ester; L-alanyl ester; nucleotide conjugate; organofluorine compound; phosphoramidate ester | antiviral drug; hepatitis C protease inhibitor; prodrug |
| jq1 compound | carboxylic ester; organochlorine compound; tert-butyl ester; thienotriazolodiazepine | angiogenesis inhibitor; anti-inflammatory agent; antineoplastic agent; apoptosis inducer; bromodomain-containing protein 4 inhibitor; cardioprotective agent; ferroptosis inducer | |
| abt-333 | dasabuvir : A member of the class of pyrimidone, which is (as the monohydrate of its sodium salt) in combination with ombitasvir, paritaprevir and ritonavir (under the trade name Viekira Pak) for treatment of chronic hepatitis C virus genotype 1 infection as well as cirrhosis of the liver. dasabuvir: an antiviral agent | aromatic ether; naphthalenes; pyrimidone; sulfonamide | antiviral drug; nonnucleoside hepatitis C virus polymerase inhibitor |
| epz-6438 | tazemetostat: a histone methyltransferase EZH2 inhibitor with antineoplastic activity | ||
| MZ1 | organic molecular entity |