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Target id: 625
Nomenclature: Glucocorticoid receptor
Systematic Nomenclature: NR3C1
Family: 3C. 3-Ketosteroid receptors
Gene and Protein Information | |||||
Species | AA | Chromosomal Location | Gene Symbol | Gene Name | Reference |
Human | 777 | 5q31.3 | NR3C1 | nuclear receptor subfamily 3 group C member 1 | 42 |
Mouse | 783 | 18 21.09 cM | Nr3c1 | nuclear receptor subfamily 3, group C, member 1 | 26 |
Rat | 795 | 18p11 | Nr3c1 | nuclear receptor subfamily 3, group C, member 1 | 69 |
Previous and Unofficial Names |
GCCR | GCR | GR | Type II glucocorticoid receptor | nuclear receptor subfamily 3, group C, member 1 (glucocorticoid receptor) | nuclear receptor subfamily 3 |
Database Links | |
Alphafold | P04150 (Hs), P06537 (Mm), P06536 (Rn) |
CATH/Gene3D | 3.30.50.10 |
ChEMBL Target | CHEMBL2034 (Hs), CHEMBL3144 (Mm), CHEMBL3368 (Rn) |
DrugBank Target | P04150 (Hs) |
Ensembl Gene | ENSG00000113580 (Hs), ENSMUSG00000024431 (Mm), ENSRNOG00000014096 (Rn) |
Entrez Gene | 2908 (Hs), 14815 (Mm), 24413 (Rn) |
Human Protein Atlas | ENSG00000113580 (Hs) |
KEGG Gene | hsa:2908 (Hs), mmu:14815 (Mm), rno:24413 (Rn) |
OMIM | 138040 (Hs) |
Orphanet | ORPHA123916 (Hs) |
Pharos | P04150 (Hs) |
RefSeq Nucleotide | NM_000176 (Hs), NM_008173 (Mm), NM_012576 (Rn) |
RefSeq Protein | NP_001019265 (Hs), NP_001191194 (Hs), NP_000167 (Hs), NP_001018661 (Hs), NP_032199 (Mm), NP_036708 (Rn) |
SynPHARM |
84619 (in complex with budesonide) 6573 (in complex with cortisol) 6570 (in complex with dexamethasone) 84539 (in complex with GSK866) 8010 (in complex with [3H]dexamethasone) |
UniProtKB | P04150 (Hs), P06537 (Mm), P06536 (Rn) |
Wikipedia | NR3C1 (Hs) |
Selected 3D Structures | |||||||||||||
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Natural/Endogenous Ligands |
aldosterone |
corticosterone |
cortisol |
deoxycorticosterone |
deoxycortisone |
Comments: Cortisol and corticosterone are the principal endogenous agonists |
Rank order of potency (Human) |
cortisol, corticosterone >> aldosterone, deoxycortisone [95] |
Download all structure-activity data for this target as a CSV file
Agonists | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Key to terms and symbols | View all chemical structures | Click column headers to sort | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Agonist Comments | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Cortisol is the main glucocorticoid in humans whereas corticosterone is the main form in rodents. Dexamethasone, cortisol and deoxycorticosterone all have high affinity for mineralocorticoid receptors as well. Note that for ciclesonide, the affinity appears low. However, this is because ciclesonide is a prodrug. The active metabolite, desisobutyrylciclesonide, has a higher affinity of 0.31nM (Ki) [4]. ZK216348 is classified as a SEGRA (Selective Glucocorticoid Receptor Agonist). C108297 is a selective glucocorticoid receptor (GR) modulator (binding Ki of 0.7 nM) that attenuates obesity by reducing caloric intake and increasing lipolysis and fat oxidation. In addition it reduces inflammation by decreasing macrophage infiltration and pro-inflammatory cytokine expression in white adipose tissue (WAT), as well as in vitro LPS-stimulated TNF-α secretion in macrophage RAW 264.7 cells [110]. |
Antagonists | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Key to terms and symbols | View all chemical structures | Click column headers to sort | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Other Binding Ligands | |||||||||||||||||||||||||||||||||||||||||||||||||||
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Immunopharmacology Comments |
The glucocorticoid receptor (GR) is a long-standing anti-inflammatory drug target, with a large number of synthetic glucocorticoids being used in the clinic for various immune-related disorders and hematological cancers. Glucocorticoids exert anti-inflammatory effects principally by repressing expression of the transcription factors AP-1 and NF-κB, and repression of pro-inflammatory genes. GR signaling facilitates an interface between the endocrine stress response and the immune system that is essential for restoring immune homeostasis following a response to stress (e.g. infection by a pathogen). Glucocorticoid-mediated immune regulation is reviewed by Cain and Cidlowski (2017) [12]. Evidence indicative of pro-inflammatory actions of glucocorticoids is scrutinised in Cruz-Topete and Cidlowski (2015) [24]. |
DNA Binding | |||||||
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DNA Binding Comments | |||||||
negative GRE [45,103] |
Co-binding Partners | |||
Name | Interaction | Effect | Reference |
C/EBPalpha | Physical, Functional | DNA binding | 96 |
Retinoid X receptor-α | Physical, Functional | DNA binding | |
HMGD | Physical, Functional | DNA binding | 7,112 |
AP1 | Physical, Functional | transactivation | 51,100,119 |
NF-κB | Physical, Functional | transactivation | 13,97 |
14-3-3ρ | Physical, Functional | cellular localization, transactivation | 58 |
HSP90 | Physical, Functional | Cellular localization | 80-82 |
HSP70 | Physical, Functional | Cellular localization | 53 |
Calreticulin | Physical, Functional | Inhibition of GR binding to GRE | |
STAT3 | Physical, Functional | Transactivation | 122 |
T-bet | Physical, Functional | Transactivation | 64 |
STAT5 | Physical, Functional | Transactivation | 102 |
p53 | Physical, Functional | Inhibition of GR binding to GRE | 121 |
Main Co-regulators | ||||||
Name | Activity | Specific | Ligand dependent | AF-2 dependent | Comments | References |
MED1 | Co-activator | No | Yes | Yes | 83 | |
NCOA2 | Co-activator | No | Yes | Yes | 43,106,113 | |
CREBBP | Co-activator | No | Yes | Yes | Histone acetyltransferase, a transcriptional cointegrator | 52 |
PTMS | Co-activator | Yes | Yes | No | Has little effect on ER-mediated transactivation. | 78 |
NCOA6 | Co-activator | No | Yes | Yes | Likely a member of multimeric complex including NIF-1. | 63 |
BAG1 | Co-repressor | No | No | Yes | A regulator of HSP70 and a co-repressor. | 62 |
NCOR1 | Co-repressor | No | No | - | 84,103 | |
SMARCD1 | Co-activator | No | No | No | Mediates interaction with SWI/SNF complex | 44 |
TADA2A | Co-activator | No | No | No | Involved in chromatin remodeling | 40 |
SMARCA1 | Co-activator | No | No | Yes | 15 |
Main Target Genes | |||||
Name | Species | Effect | Technique | Comments | References |
NR3C1 | Human | Repressed | ChIP | Also observed in rodents | 84 |
FKBP5 | Human | Activated | 109 | ||
GZMA | Human | Activated | 109 | ||
PCK1 | Human | Both | ChIP, Transient transfection | 14 | |
Dusp1 | Mouse | Activated | Transient transfection | Dusp1 is also known as MAP kinase phosphatase-1 (MKP-1) | 56 |
annexin A1 | Human | Activated | Transient transfection, other | Also known as Lipocrotin-1 | 71,93 |
Interleukin 8 | Human | Repressed | 105 | ||
TNF | Human | Repressed | 115 | ||
RCAN1 | Human | Activated | 109 | ||
PER1 | Rat | Activated | ChIP | 22 | |
TSC22D3 | Human | Activated | ChIP | 25,116 |
Tissue Distribution | ||||||||
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Tissue Distribution Comments | ||||||||
GR is expressed ubiquitously in mammals. |
Functional Assays | ||||||||||
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Physiological Consequences of Altering Gene Expression | ||||||||||
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Physiological Consequences of Altering Gene Expression Comments | ||||||||||
GR -/- mice also present the following at birth:- lungs at birth are severely atelectatic, and development is impaired from day 15.5 p.c. Newborn livers have a reduced capacity to activate genes for key gluconeogenic enzymes. Feedback regulation via the hypothalamic-pituitary-adrenal axis is severely impaired resulting in elevated levels of plasma adrenocorticotrophic hormone (15-fold) and plasma corticosterone (2.5-fold). Accordingly, adrenal glands are enlarged because of hypertrophy of the cortex, resulting in increased expression of key cortical steroid biosynthetic enzymes, such as side-chain cleavage enzyme, steroid 11 β-hydroxylase, and aldosterone synthase. Adrenal glands lack a central medulla and synthesize no adrenaline. They contain no adrenergic chromaffin cells and only scattered noradrenergic chromaffin cells even when analyzed from the earliest stages of medulla development. |
Phenotypes, Alleles and Disease Models | Mouse data from MGI | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Clinically-Relevant Mutations and Pathophysiology | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Clinically-Relevant Mutations and Pathophysiology Comments | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
In general glucocorticoid receptor (GR) polymorphisms have been associated with high blood pressure, insulin sensitivity, body mass index, increased visceral fat, and variations in tissue-specific steroid sensitivity. The N363S polymorphism of the GR results in an asparagine to serine amino acid substitution in a modulatory region of the receptor and phosphorylation of serine residues affects activation of GR target genes [28]. Many other diseases have been associated to certain GR polymorphisms, see GR SNPs. |
Biologically Significant Variants | ||||||||||
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