Glucocorticoid receptor: Difference between revisions
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{{protein |
{{protein |
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| Name = Glucocorticoid receptor (GR, NR3C1) |
| Name = Glucocorticoid receptor (GR, NR3C1) |
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| caption = Crystallographic structures of the DNA binding domain (DBD, left, {{PDB|1R4O}}) and ligand binding domain |
| caption = Crystallographic structures of the glucocorticoid receptor DNA binding domain (DBD, left, {{PDB|1R4O}} bound to DNA) and ligand binding domain [LBD, right, {{PDB2|1M2Z}} bound to [[dexamethasone]] (white sticks) and the [[nuclear receptor coactivator 2|TIF2]] [[coactivator (genetics)|coactivator]] protein (red)]. Dashed yellow lines represent [[hydrogen bond|hydrogen bonding]] interactions between the receptor and ligand. The 2D structure of dexamethasone is also depicted in the lower right hand side of the picture for reference. |
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| image = Glucocorticoid_receptor.png |
| image = Glucocorticoid_receptor.png |
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| width = 200 |
| width = 200 |
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Revision as of 20:44, 23 July 2007
| Glucocorticoid receptor (GR, NR3C1) | |||||||
|---|---|---|---|---|---|---|---|
 Crystallographic structures of the glucocorticoid receptor DNA binding domain (DBD, left, PDB: 1R4O bound to DNA) and ligand binding domain [LBD, right, 1M2Z bound to dexamethasone (white sticks) and the TIF2 coactivator protein (red)]. Dashed yellow lines represent hydrogen bonding interactions between the receptor and ligand. The 2D structure of dexamethasone is also depicted in the lower right hand side of the picture for reference. | |||||||
| Identifiers | |||||||
| Symbol | NR3C1 | ||||||
| Alt. symbols | GR, GCR, GCCR, GRL | ||||||
| NCBI gene | 2908 | ||||||
| HGNC | 7978 | ||||||
| OMIM | 138040 | ||||||
| PDB | 1P93 | ||||||
| RefSeq | NM_000176 | ||||||
| UniProt | P04150 | ||||||
| Other data | |||||||
| Locus | Chr. 5 q31-32 | ||||||
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The glucocorticoid receptor (GR) or nuclear receptor subfamily 3, group C, member 1 is a ligand-activated transcription factor that binds with high affinity to cortisol and other glucocorticoids.[1]
The GR is expressed in almost every cell in the body and regulates either directly or indirectly genes controlling a wide variety of processes including the development, metabolism, and immune response of the organism.
The GR protein is encoded by gene NR3C1 on chromosome 5 (5q31).
Structure
Like the other steroid receptors, the glucocorticoid receptor is modular in structure and contains the following domains (labeled A - F):
- A/B - N-terminal regulatory domain
- C - DNA-binding domain (DBD)
- D - hinge region
- E - ligand-binding domain (LBD)
- F - C-terminal domain
Ligand binding and response
In the absence of hormone, the glucocorticoid receptor (GR) resides in the cytosol complexed with a variety of proteins including heat shock protein 90 (hsp90), the heat shock protein 70 (hsp70) and the protein FKBP52 (FK506-binding protein 52).[2] The endogenous glucocortiod hormone cortisol diffuses through the cell membrane into the cytoplasm and binds to the glucocorticoid receptor (GR) resulitng in release of the heat shock proteins. The resulting activated form GR has two principle mechanisms of action:[3][4]
Transactivation
A direct mechanism of action in which involves homo dimerization of the receptor, translocation via active transport into the nucleus, and binding to specific DNA responsive elements activating gene transcription. This mechanism of action is referred to as transactivation. The biologic response depends on the cell type.
Transrepression
In the absence of activated GR, other transcription factors such as NF-κB or AP-1 themselves are able to transactivate target genes. However activated GR can complex with these other transcription factors and prevent them from binding their target genes and hence repress the expression of gene normally upregulated by NF-κB or AP-1. This indirect mechanism of action is referred to as transrepression.
Agonists and antagonists
Dexamethasone is an agonist, and RU486 and cyproterone are antagonists of the GR. Also, progesterone and DHEA have antagonist effects on the GR.
The GR is abnormal in familial glucocorticoid resistance.[5]
References
- ^ Lu NZ, Wardell SE, Burnstein KL, Defranco D, Fuller PJ, Giguere V, Hochberg RB, McKay L, Renoir JM, Weigel NL, Wilson EM, McDonnell DP, Cidlowski JA (2006). "International Union of Pharmacology. LXV. The pharmacology and classification of the nuclear receptor superfamily: glucocorticoid, mineralocorticoid, progesterone, and androgen receptors". Pharmacol Revl. 58 (4): 782–97. doi:10.1124/pr.58.4.9. PMID 17132855.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Pratt WB, Morishima Y, Murphy M, Harrell M (2006). "Chaperoning of glucocorticoid receptors". Handb Exp Pharmacol. 172: 111–38. PMID 16610357.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Buckingham JC (2006). "Glucocorticoids: exemplars of multi-tasking". Br J Pharmacol. 147 (Supplement 1): S258-68. doi:10.1038/sj.bjp.0706456. PMID 16402112.
- ^ Hayashi R, Wada H, Ito K, Adcock IM (2004). "Effects of glucocorticoids on gene transcription". Eur J Pharmacol. 500 (1–3): 51–62. doi:10.1016/j.ejphar.2004.07.011. PMID 15464020.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Mendonca B, Leite M, de Castro M, Kino T, Elias L, Bachega T, Arnhold I, Chrousos G, Latronico A (2002). "Female pseudohermaphroditism caused by a novel homozygous missense mutation of the GR gene". J Clin Endocrinol Metab. 87 (4): 1805–9. doi:10.1210/jc.87.4.1805. PMID 11932321.
{{cite journal}}: CS1 maint: multiple names: authors list (link)
External links
- Human Protein Reference Database
- Glucocorticoid+receptors at the U.S. National Library of Medicine Medical Subject Headings (MeSH)