Nuclear receptor

Nuclear receptors are a class of ligand activated intracelluar transcription factors which up or down regulate the expression of genes. Nuclear receptors may be classified either according to mechanism (type I or II), or sequence homology (NR subfamilies 0-6) (see respectively mechanism and homology classifications below).

Ligands
Ligands that bind to nuclear receptors include lipophilic substances such as endogenous hormones, vitamins A and D, drugs, and xenobiotic endocrine disruptors. Because the expression of a large number of genes is regulated by nuclear receptors, ligands that bind to these receptors can have profound effects on the organism. A number of nuclear receptors, referred to as orphan receptors, have no known (or at least generally agreed upon) endogenous ligands. Some of these receptors such as FXR, LXR, and PPAR bind a number of metabolic intermediates such as fatty acids, bile acids and/or sterols with relatively low affinity. These receptors hence may function as metabolic sensors. Other nuclear receptors, such as CAR and PXR appear to function as xenobiotic sensors upregulating the expression of cytochrome P450 enzymes that metabolize these xenobiotics. A few other nuclear receptors, such as the constitutive androstane receptor appear to be active in the absence of ligand. Finally a few nuclear receptors such as the short heterodimer partner (SHP; NR0B2), lack a ligand binding domain and therefore by definition cannot bind ligand.

Structure
Nuclear receptors contain the following domains:
 * A-B) N-terminal regulatory domain
 * C) DNA-binding domain (DBD). (An unusual group of NRs contain two DBDs in  tandem)
 * D) Hinge region
 * E) Ligand binding domain (LBD)
 * F) C-terminal domain

Mechanism classification
Ligand binding to type I nuclear receptors (includes members of the NR subfamily 3) results in the dissociation of heat shock proteins, homo-dimerization, translocation (i.e., active transport) from the cytoplasm into the cell nucleus, and binding to specific sequences of DNA known as hormone response elements (HRE's). The nuclear receptor/DNA complex then recruits other proteins which transcribe DNA downstream from the HRE into messenger RNA and eventually protein which causes a change in cell function.

Type II receptors (NR subfamily 1) in contrast are retained in the nucleus regardless of the ligand binding status and in addition bind as hetero-dimers (usually with RXR) to DNA.

Homology classification
The following is a list of the 48 known human nuclear receptors sorted according to sequence homology.


 * Subfamily:Group:Member: Name	(Abbreviation; NRNC Symbol - Nuclear Receptor Nomenclature Committee ) (endogenous ligand)


 * Subfamily 1: Thyroid Hormone Receptor-like
 * Group A: Thyroid hormone receptor (Thyroid hormone)
 * 1: Thyroid hormone receptor-α	(TRα; NR1A1)
 * 2: Thyroid hormone receptor-β	(TRβ; NR1A2)
 * Group B: Retinoic acid receptor	(Vitamin A and related compounds)
 * 1: Retinoic acid receptor-α	(RARα; NR1B1)
 * 2: Retinoic acid receptor-β	(RARβ; NR1B2)
 * 3: Retinoic acid receptor-γ	(RARγ; NR1B3)
 * Group C: Peroxisome proliferator-activated receptor
 * 1: Peroxisome proliferator-activated receptor-α	(PPARα; NR1C1)
 * 2: Peroxisome proliferator-activated receptor-β	(PPARβ; NR1C2)
 * 3: Peroxisome proliferator-activated receptor-γ	(PPARγ: NR1C3)
 * Group D: Rev-erb
 * 1: Rev-erbα	(Rev-erbα; NR1D1)
 * 2: Rev-erbβ	(Rev-erbβ; NR1D2)
 * Group F: Retinoid-related orphan receptor
 * 1: Retinoid-related orphan receptor-α	(RORα; NR1F1)
 * 2: Retinoid-related orphan receptor-β	(RORβ; NR1F2)
 * 3: Retinoid-related orphan receptor-γ	(RORγ; NR1F3)
 * Group H: Liver X receptor-like
 * 3: Liver X receptor-α	(LXRα; NR1H3)
 * 2: Liver X receptor-β	(LXRβ; NR1H2)
 * 4: Farnesoid X receptor	(FXR; NR1H4)
 * Group I: Vitamin D receptor-like
 * 1: Vitamin D receptor	(VDR; NR1I1)	(vitamin D)
 * 2: Pregnane X receptor	(PXR; NR1I2)
 * 3: Constitutive androstane receptor	(CAR; NR1I3)


 * Subfamily 2: Retinoid X Receptor-like
 * Group A: Hepatocyte nuclear factor-4	(HNF4)
 * 1: Hepatocyte nuclear factor-4-α	(HNF4α; NR2A1)
 * 2: Hepatocyte nuclear factor-4-γ	(HNF4γ; NR2A2)
 * Group B: Retinoid X receptor	(RXRα)
 * 1: Retinoid X receptor-α	(RXRα; NR2B1)
 * 2: Retinoid X receptor-β	(RXRβ; NR2B2)
 * 3: Retinoid X receptor-γ	(RXRγ; NR2B3)
 * Group C: Testicular receptor
 * 1: Testicular receptor 2	(TR2; NR2C1)
 * 2: Testicular receptor 4	(TR4; NR2C2)
 * Group E: TLX/PNR
 * 1: Human homologue of the Drosophila tailless gene 	(TLX; NR2E1)
 * 3: Photoreceptor-Specific Nuclear Receptor	(PNR; NR2E3)
 * Group F: COUP/EAR
 * 1: Chicken ovalbumin upstream promoter-transcription factor I	(COUP-TFI; NR2F1)
 * 2: Chicken ovalbumin upstream promoter-transcription factor II	(COUP-TFII; NR2F2)
 * 6: ERBA-related 2	(EAR2; NR2F6)


 * Subfamily 3: Estrogen Receptor-like (Steroid hormone receptor)
 * Group A: Estrogen receptor	(Sex hormone receptors; sex hormones: Estrogen)
 * 1: Estrogen receptor-α	(ERα; NR3A1)
 * 2: Estrogen receptor-β	(ERβ; NR3A2)
 * Group B: Estrogen related receptor
 * 1: Estrogen related receptor-α	(ERRα; NR3B1)
 * 2: Estrogen related receptor-β	(ERRβ; NR3B2)
 * 3: Estrogen related receptor-γ	(ERRγ; NR3B3)
 * Group C: 3-Ketosteroid receptors
 * 1: Glucocorticoid receptor	(GR; NR3C1)	(Cortisol)
 * 2: Mineralocorticoid receptor	(MR; NR3C2)	(Aldosterone)
 * 3: Progesterone receptor	(PR; NR3C3)	(Sex hormone receptor; Sex hormones: Progesterone)
 * 4: Androgen receptor	(AR; NR3C4)	(Sex hormone receptors; Sex hormones: Testosterone)


 * Subfamily 4: Nerve Growth Factor IB-like
 * Group A: NGFIB/NURR1/NOR1
 * 1: Nerve Growth factor IB	(NGFIB; NR4A1)
 * 2: Nuclear receptor related 1	(NURR1; NR4A2)
 * 3: Neuron-derived orphan receptor 1 (NOR1; NR4A3)


 * Subfamily 5: Steroidogenic Factor-like
 * Group A: SF1/LRH1
 * 1: Steroidogenic factor 1	(SF1; NR5A1)
 * 2: Liver receptor homolog 1 	(LRH1; NR5A2)


 * Subfamily 6: Germ Cell Nuclear Factor-like
 * Group A: GCN1
 * 1: Germ cell nuclear factor	(GCN1; NR6A1)


 * Subfamily 0: Miscellaneous
 * Group B: DAX/SHP
 * 1: Dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1 (DAX-1; NR0B1)
 * 2: Short heterodimer partner	(SHP; NR0B2)


 * Subfamily 7: Nuclear receptors with two DNA binding domains (2DBD-NR) (A novel subfamily)