Glucocorticoid receptor

Chr 5: 142.64 - 142.8 Mb

Nuclear receptor subfamily 3, group C, member 1 (glucocorticoid receptor)
Crystallographic structures of the glucocorticoid receptor DNA binding domain (DBD, left, (white sticks) and the protein (red)]. Dashed yellow lines represent PDB 1R4O bound to DNA) and ligand binding domain [LBD, right, 1M2Z bound to dexamethasoneTIF2 coactivatorhydrogen 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.
Available structures: 1gdc, 1glu, 1m2z, 1nhz, 1p93, 1r4o, 1r4r, 1rgd, 2gda
Identifiers
Symbols	NR3C1; GCCR; GCR; GR; GRL
External IDs	OMIM: 138040 MGI: 95824 HomoloGene: 30960
Gene ontology Molecular function: • transcription factor activity • glucocorticoid receptor activity • steroid binding • protein binding • zinc ion binding • lipid binding • sequence-specific DNA binding • metal ion binding Cellular component: • nucleus • cytoplasm • mitochondrial matrix Biological process: • regulation of transcription, DNA-dependent • transcription from RNA polymerase II promoter • inflammatory response • signal transduction • sex determination
RNA expression pattern
Orthologs
	Human	Mouse
Entrez	2908	14815
Ensembl	ENSG00000113580	ENSMUSG0000002443
Uniprot	P04150	Q05DD1
Refseq	NM_000176 (mRNA) NP_000167 (protein)	NM_008173 (mRNA) NP_032199 (protein)
Chr 5: 142.64 - 142.8 Mb	Chr 18: 39.54 - 39.62 Mb
Pubmed search

The glucocorticoid receptor (GR, or GCR) also known as NR3C1 (nuclear receptor subfamily 3, group C, member 1) is a ligand-activated transcription factor that binds with high affinity to cortisol and other glucocorticoids.

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). The endogenous glucocortiod hormone cortisol diffuses through the cell membrane into the cytoplasm and binds to the glucocorticoid receptor (GR) resulting in release of the heat shock proteins. The resulting activated form GR has two principal mechanisms of action, transactivation and transrepression, described below.

Transactivation

A direct mechanism of action involves homodimerization 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 genes that are 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.