RAR-related orphan receptor-γ
Target id: 600
Nomenclature: RAR-related orphan receptor-γ
Systematic Nomenclature: NR1F3
Contents:
- Gene and Protein Information
- Previous and Unofficial Names
- Database Links
- Selected 3D Structures
- Natural/Endogenous Ligands
- Agonists
- Antagonists
- Allosteric Modulators
- Immunopharmacology Comments
- Immuno Process Associations
- DNA Binding
- Co-binding Partners
- Main Co-regulators
- Tissue Distribution
- Physiological Consequences of Altering Gene Expression
- Phenotypes, Alleles and Disease Models
- Biologically Significant Variants
- References
- Contributors
- How to cite this page
Gene and Protein Information  |
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| Species | AA | Chromosomal Location | Gene Symbol | Gene Name | Reference |
| Human | 518 | 1q21 | RORC | RAR related orphan receptor C | 12 |
| Mouse | 516 | 3 F2.1 | Rorc | RAR-related orphan receptor gamma | 25 |
| Rat | - | 2q34 | Rorc | RAR-related orphan receptor C | |
| Gene and Protein Information Comments | |||||
| Two protein isoforms, produced by alternative promoter usage, are expressed from the human RORC gene. Isoform 1 (RORC1) is the 518 amino acid full-length product. Isoform 2 (RORC2 or RORγt) is shorter, missing the first 21 amino acids of isoform 1 and having amino acids 22-24 (HTS) replaced by MRT. Isoform 2 is exclusively expressed by immature thymocytes. | |||||
| Previous and Unofficial Names |
| nuclear receptor ROR-gamma | nuclear receptor RZR-gamma | RORC2 | RORγ | RORγt | RZRγ | Thor | thymus orphan receptor | TOR |
| Database Links |
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| Alphafold | P51449 (Hs), P51450 (Mm) |
| CATH/Gene3D | 3.30.50.10 |
| ChEMBL Target | CHEMBL1741186 (Hs), CHEMBL1293231 (Mm) |
| Ensembl Gene | ENSG00000143365 (Hs), ENSMUSG00000028150 (Mm), ENSRNOG00000020836 (Rn) |
| Entrez Gene | 6097 (Hs), 19885 (Mm), 368158 (Rn) |
| Human Protein Atlas | ENSG00000143365 (Hs) |
| KEGG Gene | hsa:6097 (Hs), mmu:19885 (Mm), rno:368158 (Rn) |
| OMIM | 602943 (Hs) |
| Pharos | P51449 (Hs) |
| RefSeq Nucleotide | NM_001001523 (Hs), NM_005060 (Hs), NM_011281 (Mm) |
| RefSeq Protein | NP_001001523 (Hs), NP_005051 (Hs), NP_035411 (Mm) |
| SynPHARM |
6597 (in complex with 25-hydroxycholesterol) 84981 (in complex with TAK-828F) |
| UniProtKB | P51449 (Hs), P51450 (Mm) |
| Wikipedia | RORC (Hs) |
| Selected 3D Structures |
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| Natural/Endogenous Ligands |
| 25-hydroxycholesterol |
| Comments: Orphan |
Download all structure-activity data for this target as a CSV file 
| Agonists |
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| Key to terms and symbols | View all chemical structures | Click column headers to sort | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Agonist Comments | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Even although no ligands have been identified, hydroxycholesterols have been shown to promote the recruitment of coactivators by RORγ using biochemical assays [15]. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Antagonists |
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| Antagonist Comments | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Both ALRT 1550 and all-trans retinoic acid partially inhibit RORγ transcriptional activity. | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Allosteric Modulators | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Immunopharmacology Comments |
| RORγ is a nuclear receptor transcription factor that acts as an immune cell master control switch (most likely associated with expression of the RORγt isoform). This receptor is an essential regulator of type 17 effector T cell differentiation and function. RORγt inhibitors (antagonists and inverse agonists) [3,10,24,31] are in development for the treatment of autoimmune diseases such as psoriasis and rheumatoid arthritis [2,14]. Inverse agonists block RORγt-driven development and differentiation of IL-17 producing Th17 cells to reduce inflammation. Examples include AZD0284 (see the ACS webinar Psoriasis: Treatment and Novel Approaches) and GNE-3500 [8]. Development of VTP-43742 [10], Allergan's RORγ inverse agonist, was terminated in early 2018 due to safety issues detected in their Phase 2 psoriasis trial. As immuno-oncology candidates, RORγ agonists are being studied for their potential to improve immune detection/destruction of cancer cells [13]. For example, Lycera's orally active agent cintirorgon is being evaluated in early phase clinical trial NCT02929862 in patients with locally advanced or metastatic solid tumours. |
| Immuno Process Associations | ||
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| DNA Binding |
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| DNA Binding Comments | |||||||
| It has been shown that mouse RORγ does not recognise the classical ROREs but binds with high affinity as a homodimer to DR4 and DR5 elements. | |||||||
| Co-binding Partners |
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| Name | Interaction | Effect | Reference |
| Mi-2beta | Physical, Functional | Mi-2beta: A yeast two-hybrid screen with Y190 yeast cells under stringent conditions resulted in the identification of CHD4, also known as Mi-2beta, as a RORgamma-interacting protein. This interaction was confirmed by GST pull-down assays. This interaction occurred within the middle regulatory region (amino acids 719-1164) of Mi-2beta. Transfection of Gal4-RORgamma into HeLa cells resulted in constitutive transactivation of the MH100-tk-luc reporter. The addition of Mi-2beta resulted in a dramatic 50% decrease in Gal4-RORgamma-mediated transactivation. These data demonstrate that RORgamma forms a protein-protein interaction with the regulatory region of Mi-2beta, resulting in inhibition of RORgamma transcriptional activity. | 16 |
| Main Co-regulators |
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| Name | Activity | Specific | Ligand dependent | AF-2 dependent | Comments | References |
| NCOA1 | Co-activator | No | No | Yes | 20 | |
| HR | Co-repressor | No | Yes | Yes | 22 | |
| Tissue Distribution
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| Tissue Distribution Comments | ||||||||||
| In the human tissues RORγ was shown to be highly expressed as a 3.2 kb mRNA. In thymus, two other transcripts at 7.2 and 5.2 kb were also detected. In mouse, other authors found a predominant expression in thymus as in other tissues such as liver, heart, tongue, muscle, and diaphragm. Notably, no expression was found in spleen, or bone marrow. The major transcript is found at 2.5 kb but a 3.5 kb form is detected in several organs such as thymus. The same study reports expression in a number of mammalian cell lines. Recently, it has been shown that during fetal life, the nuclear hormone receptor RORγt is expressed exclusively in and is required for the generation of lymphoid tissue inducer cells [6,33]. | ||||||||||
| Physiological Consequences of Altering Gene Expression
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| Phenotypes, Alleles and Disease Models
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Mouse data from MGI | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Biologically Significant Variants
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References
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