Nuclear receptor

Crystallographic structure of a heterodimer of the nuclear receptors PPAR-γ (green) and RXR-α (cyan) bound to double stranded DNA (magenta) and two molecules of the NCOA2 coactivator (red). The PPAR-γ antagonist GW9662 and RXR-α agonist retinoic acid are depicted as space-filling models (carbon = white, oxygen = red, nitrogen = blue, chlorine = green).^[1]

In the field of molecular biology, nuclear receptors are a class of proteins found within cells that are responsible for sensing steroid and thyroid hormones and certain other molecules. In response, these receptors work with other proteins to regulate the expression of specific genes, thereby controlling the development, homeostasis, and metabolism of the organism.

Nuclear receptors have the ability to directly bind to DNA and regulate the expression of adjacent genes, hence these receptors are classified as transcription factors.^[2][3] The regulation of gene expression by nuclear receptors generally only happens when a ligand — a molecule that affects the receptor's behavior — is present. More specifically, ligand binding to a nuclear receptor results in a conformational change in the receptor, which, in turn, activates the receptor, resulting in up-regulation or down-regulation of gene expression.

A unique property of nuclear receptors that differentiates them from other classes of receptors is their ability to directly interact with and control the expression of genomic DNA. As a consequence, nuclear receptors play key roles in both embryonic development and adult homeostasis. As discussed below, nuclear receptors may be classified according to either mechanism^[4][5] or homology.^[6][7]

Species distribution

Nuclear receptors are specific to metazoans (animals) and are not found in protists, algae, fungi, or plants.^[8] Amongst the early-branching animal lineages with sequenced genomes, two have been reported from the sponge Amphimedon queenslandica, two from the ctenophore Mnemiopsis leidyi^[9] four from the placozoan Trichoplax adhaerens and 17 from the cnidarian Nematostella vectensis.^[10] There are 270 nuclear receptors in the nematode C. elegans alone.^[11] Humans, mice, and rats have respectively 48, 49, and 47 nuclear receptors each.^[12]

Ligands

Structures of selected endogenous nuclear receptor ligands and the name of the receptor that each binds to.

Ligands that bind to and activate nuclear receptors include lipophilic substances such as endogenous hormones, vitamins A and D, and xenobiotic endocrine disruptors. Because the expression of a large number of genes is regulated by nuclear receptors, ligands that activate these receptors can have profound effects on the organism. Many of these regulated genes are associated with various diseases, which explains why the molecular targets of approximately 13% of U.S. Food and Drug Administration (FDA) approved drugs are nuclear receptors.^[13]

A number of nuclear receptors, referred to as orphan receptors,^[14] 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 up-regulating the expression of cytochrome P450 enzymes that metabolize these xenobiotics.^[15]

Structure

Nuclear receptors are modular in structure and contain the following domains:^[16][17]

• A-B) N-terminal regulatory domain: Contains the activation function 1 (AF-1) whose action is independent of the presence of ligand.^[18] The transcriptional activation of AF-1 is normally very weak, but it does synergize with AF-2 in the E-domain (see below) to produce a more robust upregulation of gene expression. The A-B domain is highly variable in sequence between various nuclear receptors.
• C) DNA-binding domain (DBD): Highly conserved domain containing two zinc fingers that binds to specific sequences of DNA called hormone response elements (HRE).
• D) Hinge region: Thought to be a flexible domain that connects the DBD with the LBD. Influences intracellular trafficking and subcellular distribution.
• E) Ligand binding domain (LBD): Moderately conserved in sequence and highly conserved in structure between the various nuclear receptors. The structure of the LBD is referred to as an alpha helical sandwich fold in which three anti parallel alpha helices (the "sandwich filling") are flanked by two alpha helices on one side and three on the other (the "bread"). The ligand binding cavity is within the interior of the LBD and just below three anti parallel alpha helical sandwich "filling". Along with the DBD, the LBD contributes to the dimerization interface of the receptor and in addition, binds coactivator and corepressor proteins. The LBD also contains the activation function 2 (AF-2) whose action is dependent on the presence of bound ligand.^[18]
• F) C-terminal domain: Highly variable in sequence between various nuclear receptors.

Structural Organization of Nuclear Receptors Top – Schematic 1D amino acid sequence of a nuclear receptor. Bottom – 3D structures of the DBD (bound to DNA) and LBD (bound to hormone) regions of the nuclear receptor. The structures shown are of the estrogen receptor. Experimental structures of N-terminal domain (A/B), hinge region (D), and C-terminal domain (F) have not been determined therefore are represented by red, purple, and orange dashed lines, respectively.

DNA binding domain (DBD) Crystallographic structure of the human progesterone receptor DNA-binding domain dimer (cyan and green) complexed with double strained DNA (magenta). Zinc atoms of are depicted as grey spheres.[19] Identifiers Symbol zf-C4 Pfam PF00105 InterPro IPR001628 SMART SM00399 PROSITE PDOC00031 SCOP 1hra CDD cd06916 Available protein structures: Pfam structures PDB RCSB PDB; PDBe PDBsum structure summary

Ligand-binding domain (LBD) Crystallographic structure of the ligand binding domain of the human RORγ (rainbow colored, N-terminus = blue, C-terminus = red) complexed with 25-hydroxycholesterol (space-filling model (carbon = white, oxygen = red) and the NCOA2 coactivator (magneta).[20] Identifiers Symbol Hormone_recep Pfam PF00104 InterPro IPR000536 SMART SM00430 SCOP 1lbd CDD cd06157 Available protein structures: Pfam structures PDB RCSB PDB; PDBe PDBsum structure summary

Mechanism of action

Mechanism nuclear receptor action. This figure depicts the mechanism of a class I nuclear receptor (NR) that, in the absence of ligand, is located in the cytosol. Hormone binding to the NR triggers dissociation of heat shock proteins (HSP), dimerization, and translocation to the nucleus, where the NR binds to a specific sequence of DNA known as a hormone response element (HRE). The nuclear receptor DNA complex in turn recruits other proteins that are responsible for transcription of downstream DNA into mRNA, which is eventually translated into protein, which results in a change in cell function.

Mechanism nuclear receptor action. This figure depicts the mechanism of a class II nuclear receptor (NR), which, regardless of ligand-binding status, is located in the nucleus bound to DNA. For the purpose of illustration, the nuclear receptor shown here is the thyroid hormone receptor (TR) heterodimerized to the RXR. In the absence of ligand, the TR is bound to corepressor protein. Ligand binding to TR causes a dissociation of corepressor and recruitment of coactivator protein, which, in turn, recruits additional proteins such as RNA polymerase that are responsible for transcription of downstream DNA into RNA and eventually protein, which results in a change in cell function.

Nuclear receptors (NRs) may be classified into two broad classes according to their mechanism of action and subcellular distribution in the absence of ligand.

Small lipophilic substances such as natural hormones diffuse past the cell membrane and bind to nuclear receptors located in the cytosol (type I NR) or nucleus (type II NR) of the cell. This causes a change in the conformation of the receptor, which, depending on the mechanistic class (type I or II), triggers a number of down stream events that eventually results in up or down regulation of gene expression. In addition, two additional classes, type III which are a variant of type I, and type IV that bind DNA as monomers have also been defined.^[4]

Accordingly, nuclear receptors may be subdivided into the following four mechanistic classes:^[4][5]

Type I

Ligand binding to type I nuclear receptors in the cytosol 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 (HREs). Type I nuclear receptors bind to HREs consisting of two half-sites separated by a variable length of DNA, and the second half-site has a sequence inverted from the first (inverted repeat). Type I nuclear receptors include members of subfamily 3, such as the androgen receptor, estrogen receptors, glucocorticoid receptor, and progesterone receptor.^[21]

It has been noted that some of the NR subfamily 2 nuclear receptors may bind to direct repeat instead of inverted repeat HREs. In addition, some nuclear receptors that bind either as monomers or dimers, with only a single DNA binding domain of the receptor attaching to a single half site HRE. As of now, these nuclear receptors are considered orphan receptors, as their endogenous ligands still unknown.

The nuclear receptor/DNA complex then recruits other proteins that transcribe DNA downstream from the HRE into messenger RNA and eventually protein, which causes a change in cell function.

Type II

Type II receptors, in contrast to type I, are retained in the nucleus regardless of the ligand binding status and in addition bind as hetero-dimers (usually with RXR) to DNA. In the absence of ligand, type II nuclear receptors are often complexed with corepressor proteins. Ligand binding to the nuclear receptor causes dissociation of corepressor and recruitment of coactivator proteins. Additional proteins including RNA polymerase are then recruited to the NR/DNA complex that transcribe DNA into messenger RNA.

Type II nuclear receptors include principally subfamily 1, for example the retinoic acid receptor, retinoid X receptor and thyroid hormone receptor.^[22]

Type III

Type III nuclear receptors (principally NR subfamily 2) are similar to type I receptors in that both classes bind to DNA as homodimers. However, type III nuclear receptors, in contrast to type I, bind to direct repeat instead of inverted repeat HREs.

Type IV

Type IV nuclear receptors bind either as monomers or dimers, but only a single DNA binding domain of the receptor binds to a single half site HRE. Examples of type IV receptors are found in most of the NR subfamilies.

Coregulatory proteins

Main article: nuclear receptor coregulators

Nuclear receptors bound to hormone response elements recruit a significant number of other proteins (referred to as transcription coregulators) that facilitate or inhibit the transcription of the associated target gene into mRNA.^[23][24] The function of these coregulators are varied and include chromatin remodeling (making the target gene either more or less accessible to transcription) or a bridging function to stabilize the binding of other coregulatory proteins.

Coactivators

Binding of agonist ligands (see section below) to nuclear receptors induces a conformation of the receptor that preferentially binds coactivator proteins. These proteins often have an intrinsic histone acetyltransferase (HAT) activity, which weakens the association of histones to DNA, and therefore promotes gene transcription.

Corepressors

Binding of antagonist ligands to nuclear receptors in contrast induces a conformation of the receptor that preferentially binds corepressor proteins. These proteins, in turn, recruit histone deacetylases (HDACs), which strengthens the association of histones to DNA, and therefore represses gene transcription.

Agonism vs antagonism

Stuctural basis for the mechanism of nuclear receptor agonist and antagonist action.^[25] The structures shown here are of the ligand binding domain (LBD) of the estrogen receptor (green cartoon diagram) complexed with either the agonist diethylstilbestrol (top, PDB 3ERD) or antagonist 4-hydroxytamoxifen (bottom, 3ERT). The ligands are depicted as space filling spheres (white = carbon, red = oxygen). When an agonist is bound to a nuclear receptor, the C-terminal alpha helix of the LDB (H12; light blue) is positioned such that a coactivator protein (red) can bind to the surface of the LBD. Shown here is just a small part of the coactivator protein, the so called NR box containing the LXXLL amino acid sequence motif.^[26] Antagonists occupy the same ligand binding cavity of the nuclear receptor. However antagonist ligands in addition have a sidechain extension which sterically displaces H12 to occupy roughly the same position in space as coactivators bind. Hence coactivator binding to the LBD is blocked.

Depending on the receptor involved, the chemical structure of the ligand and the tissue that is being affected, nuclear receptor ligands may display dramatically diverse effects ranging in a spectrum from agonism to antagonism to inverse agonism.^[27]

Agonists

The activity of endogenous ligands (such as the hormones estradiol and testosterone) when bound to their cognate nuclear receptors is normally to upregulate gene expression. This stimulation of gene expression by the ligand is referred to as an agonist response. The agonistic effects of endogenous hormones can also be mimicked by certain synthetic ligands, for example, the glucocorticoid receptor anti-inflammatory drug dexamethasone. Agonist ligands work by inducing a conformation of the receptor which favors coactivator binding (see upper half of the figure to the right).

Antagonists

Other synthetic nuclear receptor ligands have no apparent effect on gene transcription in the absence of endogenous ligand. However they block the effect of agonist through competitive binding to the same binding site in the nuclear receptor. These ligands are referred to as antagonists. An example of antagonistic nuclear receptor drug is mifepristone which binds to the glucocorticoid and progesterone receptors and therefore blocks the activity of the endogenous hormones cortisol and progesterone respectively. Antagonist ligands work by inducing a conformation of the receptor which prevents coactivator and promotes corepressor binding (see lower half of the figure to the right).

Inverse agonists

Finally, some nuclear receptors promote a low level of gene transcription in the absence of agonists (also referred to as basal or constitutive activity). Synthetic ligands which reduce this basal level of activity in nuclear receptors are known as inverse agonists.^[28]

Selective receptor modulators

A number of drugs that work through nuclear receptors display an agonist response in some tissues and an antagonistic response in other tissues. This behavior may have substantial benefits since it may allow retaining the desired beneficial therapeutic effects of a drug while minimizing undesirable side effects. Drugs with this mixed agonist/antagonist profile of action are referred to as selective receptor modulators (SRMs). Examples include Selective Androgen Receptor Modulators (SARMs), Selective Estrogen Receptor Modulators (SERMs) and Selective Progesterone Receptor Modulators (SPRMs). The mechanism of action of SRMs may vary depending on the chemical structure of the ligand and the receptor involved, however it is thought that many SRMs work by promoting a conformation of the receptor that is closely balanced between agonism and antagonism. In tissues where the concentration of coactivator proteins is higher than corepressors, the equilibrium is shifted in the agonist direction. Conversely in tissues where corepressors dominate, the ligand behaves as an antagonist.^[29]

Alternative mechanisms

Phylogenetic tree of human nuclear receptors

Transrepression

The most common mechanism of nuclear receptor action involves direct binding of the nuclear receptor to a DNA hormone response element. This mechanism is referred to as transactivation. However some nuclear receptors not only have the ability to directly bind to DNA, but also to other transcription factors. This binding often results in deactivation of the second transcription factor in a process known as transrepression.^[30] One example of a nuclear receptor that are able to transrepress is the glucocorticoid receptor (GR). Furthermore certain GR ligands known as Selective Glucocorticoid Receptor Agonists (SEGRAs) are able to activate GR in such a way that GR more strongly transrepresses than transactivates. This selectivity increases the separation between the desired antiinflammatory effects and undesired metabolic side effects of these selective glucocorticoids.

Non-genomic

The classical direct effects of nuclear receptors on gene regulation normally takes hours before a functional effect is seen in cells because of the large number of intermediate steps between nuclear receptor activation and changes in protein expression levels. However it has been observed that some effects from the application of hormones such as estrogen occur within minutes which is inconsistent with the classical mechanism of nuclear receptor action. While the molecular target for these non-genomic effects of nuclear receptors has not been conclusively demonstrated, it has been hypothesized that there are variants of nuclear receptors which are membrane associated instead of being localized in the cytosol or nucleus. Furthermore these membrane associated receptors function through alternative signal transduction mechanisms not involving gene regulation.^[31][32]

Family members

The following is a list of the 48 known human nuclear receptors^[12] categorized according to sequence homology.^[6][7]

Subfamily		Group		Member
				NRNC Symbol[6]	Abbreviation	Name	Gene	Ligand(s)
1	Thyroid Hormone Receptor-like	A	Thyroid hormone receptor	NR1A1	TRα	Thyroid hormone receptor-α	THRA	thyroid hormone
				NR1A2	TRβ	Thyroid hormone receptor-β	THRB
		B	Retinoic acid receptor	NR1B1	RARα	Retinoic acid receptor-α	RARA	vitamin A and related compounds
				NR1B2	RARβ	Retinoic acid receptor-β	RARB
				NR1B3	RARγ	Retinoic acid receptor-γ	RARG
		C	Peroxisome proliferator-activated receptor	NR1C1	PPARα	Peroxisome proliferator-activated receptor-α	PPARA	fatty acids, prostaglandins
				NR1C2	PPAR-β/δ	Peroxisome proliferator-activated receptor-β/δ	PPARD
				NR1C3	PPARγ	Peroxisome proliferator-activated receptor-γ	PPARG
		D	Rev-ErbA	NR1D1	Rev-ErbAα	Rev-ErbAα	NR1D1	heme
				NR1D2	Rev-ErbAβ	Rev-ErbAα	NR1D2
		F	RAR-related orphan receptor	NR1F1	RORα	RAR-related orphan receptor-α	RORA	cholesterol, ATRA
				NR1F2	RORβ	RAR-related orphan receptor-β	RORB
				NR1F3	RORγ	RAR-related orphan receptor-γ	RORC
		H	Liver X receptor-like	NR1H3	LXRα	Liver X receptor-α	NR1H3	oxysterols
				NR1H2	LXRβ	Liver X receptor-β	NR1H2
				NR1H4	FXR	Farnesoid X receptor	NR1H4
		I	Vitamin D receptor-like	NR1I1	VDR	Vitamin D receptor	VDR	vitamin D
				NR1I2	PXR	Pregnane X receptor	NR1I2	xenobiotics
				NR1I3	CAR	Constitutive androstane receptor	NR1I3	androstane
		X	NRs with two DNA binding domains[33][34]	NR1X1	2DBD-NRα
				NR1X2	2DBD-NRβ
				NR1X3	2DBD-NRγ
2	Retinoid X Receptor-like	A	Hepatocyte nuclear factor-4	NR2A1	HNF4α	Hepatocyte nuclear factor-4-α	HNF4A	fatty acids
				NR2A2	HNF4γ	Hepatocyte nuclear factor-4-γ	HNF4G
		B	Retinoid X receptor	NR2B1	RXRα	Retinoid X receptor-α	RXRA	retinoids
				NR2B2	RXRβ	Retinoid X receptor-β	RXRB
				NR2B3	RXRγ	Retinoid X receptor-γ	RXRG
		C	Testicular receptor	NR2C1	TR2	Testicular receptor 2	NR2C1
				NR2C2	TR4	Testicular receptor 4	NR2C2
		E	TLX/PNR	NR2E1	TLX	Homologue of the Drosophila tailless gene	NR2E1
				NR2E3	PNR	Photoreceptor cell-specific nuclear receptor	NR2E3
		F	COUP/EAR	NR2F1	COUP-TFI	Chicken ovalbumin upstream promoter-transcription factor I	NR2E1
				NR2F2	COUP-TFII	Chicken ovalbumin upstream promoter-transcription factor II	NR2F2
				NR2F6	EAR-2	V-erbA-related	NR2F6
3	Estrogen Receptor-like	A	Estrogen receptor	NR3A1	ERα	Estrogen receptor-α	ESR1	estrogens
				NR3A2	ERβ	Estrogen receptor-β	ESR2
		B	Estrogen related receptor	NR3B1	ERRα	Estrogen-related receptor-α	ESRRA
				NR3B2	ERRβ	Estrogen-related receptor-β	ESRRB
				NR3B3	ERRγ	Estrogen-related receptor-γ	ESRRG
		C	3-Ketosteroid receptors	NR3C1	GR	Glucocorticoid receptor	NR3C1	cortisol
				NR3C2	MR	Mineralocorticoid receptor	NR3C2	aldosterone
				NR3C3	PR	Progesterone receptor	PGR	progesterone
				NR3C4	AR	Androgen receptor	AR	testosterone
4	Nerve Growth Factor IB-like	A	NGFIB/NURR1/NOR1	NR4A1	NGFIB	Nerve Growth factor IB	NR4A1
				NR4A2	NURR1	Nuclear receptor related 1	NR4A2
				NR4A3	NOR1	Neuron-derived orphan receptor 1	NR4A3
5	Steroidogenic Factor-like	A	SF1/LRH1	NR5A1	SF1	Steroidogenic factor 1	NR5A1	phosphatidylinositols
				NR5A2	LRH-1	Liver receptor homolog-1	NR5A2	phosphatidylinositols
6	Germ Cell Nuclear Factor-like	A	GCNF	NR6A1	GCNF	Germ cell nuclear factor	NR6A1
0	Miscellaneous	A	DAX/SHP	NR0B1	DAX1	Dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1	NR0B1
				NR0B2	SHP	Small heterodimer partner	NR0B2

History

Below is a brief selection of key events in the history of nuclear receptor research.^[35]

• 1905 – Ernest Starling coined the word hormone
• 1926 – Edward Calvin Kendall and Tadeus Reichstein isolated and determined the structures of cortisone and thyroxine
• 1929 – Adolf Butenandt and Edward Adelbert Doisy – independently isolated and determined the structure of estrogen
• 1958 – Elwood Jensen – isolated the estrogen receptor
• 1980s – cloning of the estrogen, glucocorticoid, and thyroid hormone receptors by Pierre Chambon, Ronald Evans, and Björn Vennström respectively
• 2004 – Pierre Chambon, Ronald Evans, and Elwood Jensen were awarded the Albert Lasker Award for Basic Medical Research, an award that frequently precedes a Nobel Prize in Medicine

See also

• Receptor
• Intracellular receptor
• Steroid hormone receptor
• Transcription factor
• Obesogen

References

1. ^ PDB 3E00; Chandra V, Huang P, Hamuro Y, Raghuram S, Wang Y, Burris TP, Rastinejad F. Structure of the intact PPAR-gamma-RXR-alpha nuclear receptor complex on DNA. Nature. 2008:350–356. doi:10.1038/nature07413. PMID 18971932.
2. ^ Evans RM. The steroid and thyroid hormone receptor superfamily. Science. 1988;240(4854):889–95. doi:10.1126/science.3283939. PMID 3283939.
3. ^ Olefsky JM. Nuclear receptor minireview series. J. Biol. Chem.. 2001;276(40):36863–4. doi:10.1074/jbc.R100047200. PMID 11459855.
4. ^ ^{a b c} Mangelsdorf DJ, Thummel C, Beato M, Herrlich P, Schutz G, Umesono K, Blumberg B, Kastner P, Mark M, Chambon P, Evans RM. The nuclear receptor superfamily: the second decade. Cell. 1995;83(6):835–9. doi:10.1016/0092-8674(95)90199-X. PMID 8521507.
5. ^ ^{a b} Novac N, Heinzel T. Nuclear receptors: overview and classification. Curr Drug Targets Inflamm Allergy. 2004;3(4):335–46. doi:10.2174/1568010042634541. PMID 15584884.
6. ^ ^{a b c} Nuclear Receptors Nomenclature Committee. A unified nomenclature system for the nuclear receptor superfamily. Cell. 1999;97(2):161–3. doi:10.1016/S0092-8674(00)80726-6. PMID 10219237.
7. ^ ^{a b} Laudet V. Evolution of the nuclear receptor superfamily: early diversification from an ancestral orphan receptor. J. Mol. Endocrinol.. 1997;19(3):207–26. doi:10.1677/jme.0.0190207. PMID 9460643.
8. ^ Escriva H, Langlois MC, Mendonça RL, Pierce R, Laudet V. Evolution and diversification of the nuclear receptor superfamily. Annals of the New York Academy of Sciences. 1998;839:143–6. doi:10.1111/j.1749-6632.1998.tb10747.x. PMID 9629140.
9. ^ Reitzel AM, Pang K, Ryan JF, Mullikin JC, Martindale MQ, Baxevanis AD, Tarrant AM. Nuclear receptors from the ctenophore Mnemiopsis leidyi lack a zinc-finger DNA-binding domain: lineage-specific loss or ancestral condition in the emergence of the nuclear receptor superfamily?. Evodevo. 2011;2(1):3. doi:10.1186/2041-9139-2-3. PMID 21291545.
10. ^ Bridgham JT, Eick GN, Larroux C, Deshpande K, Harms MJ, Gauthier ME, Ortlund EA, Degnan BM, Thornton JW. Protein evolution by molecular tinkering: diversification of the nuclear receptor superfamily from a ligand-dependent ancestor. PLoS Biol.. 2010;8(10). doi:10.1371/journal.pbio.1000497. PMID 20957188.
11. ^ Sluder AE, Maina CV. Nuclear receptors in nematodes: themes and variations. Trends in Genetics : TIG. 2001;17(4):206–13. doi:10.1016/S0168-9525(01)02242-9. PMID 11275326.
12. ^ ^{a b} Zhang Z, Burch PE, Cooney AJ, Lanz RB, Pereira FA, Wu J, Gibbs RA, Weinstock G, Wheeler DA. Genomic analysis of the nuclear receptor family: new insights into structure, regulation, and evolution from the rat genome. Genome Res. 2004;14(4):580–90. doi:10.1101/gr.2160004. PMID 15059999.
13. ^ Overington JP, Al-Lazikani B, Hopkins AL. How many drug targets are there?. Nature reviews. Drug discovery. 2006;5(12):993–6. doi:10.1038/nrd2199. PMID 17139284.
14. ^ Benoit G, Cooney A, Giguere V, Ingraham H, Lazar M, Muscat G, Perlmann T, Renaud JP, Schwabe J, Sladek F, Tsai MJ, Laudet V. International Union of Pharmacology. LXVI. Orphan nuclear receptors. Pharmacol. Rev.. 2006;58(4):798–836. doi:10.1124/pr.58.4.10. PMID 17132856.
15. ^ Mohan R, Heyman RA. Orphan nuclear receptor modulators. Curr Top Med Chem. 2003;3(14):1637–47. doi:10.2174/1568026033451709. PMID 14683519.
16. ^ Kumar R, Thompson EB. The structure of the nuclear hormone receptors. Steroids. 1999;64(5):310–9. doi:10.1016/S0039-128X(99)00014-8. PMID 10406480.
17. ^ Klinge CM. Estrogen receptor interaction with co-activators and co-repressors. Steroids. 2000;65(5):227–51. doi:10.1016/S0039-128X(99)00107-5. PMID 10751636.
18. ^ ^{a b} Wärnmark A, Treuter E, Wright AP, Gustafsson J-Å. Activation functions 1 and 2 of nuclear receptors: molecular strategies for transcriptional activation. Mol. Endocrinol.. 2003;17(10):1901–9. doi:10.1210/me.2002-0384. PMID 12893880.
19. ^ PDB 2C7A; Roemer SC, Donham DC, Sherman L, Pon VH, Edwards DP, Churchill ME. Structure of the progesterone receptor-deoxyribonucleic acid complex: novel interactions required for binding to half-site response elements. Mol. Endocrinol.. 2006;20(12):3042–52. doi:10.1210/me.2005-0511. PMID 16931575.
20. ^ PDB 3L0L; Jin L, Martynowski D, Zheng S, Wada T, Xie W, Li Y. Structural basis for hydroxycholesterols as natural ligands of orphan nuclear receptor RORgamma. Mol. Endocrinol.. 2010;24(5):923–9. doi:10.1210/me.2009-0507. PMID 20203100.
21. ^ Linja MJ, Porkka KP, Kang Z, et al.. Expression of androgen receptor coregulators in prostate cancer. Clin. Cancer Res.. 2004;10(3):1032–40. doi:10.1158/1078-0432.CCR-0990-3. PMID 14871982.
22. ^ Klinge CM, Bodenner DL, Desai D, Niles RM, Traish AM. Binding of type II nuclear receptors and estrogen receptor to full and half-site estrogen response elements in vitro. Nucleic Acids Res.. 1997;25(10):1903–12. doi:10.1093/nar/25.10.1903. PMID 9115356.
23. ^ Glass CK, Rosenfeld MG. The coregulator exchange in transcriptional functions of nuclear receptors. Genes Dev. 2000;14(2):121–41. doi:10.1101/gad.14.2.121. PMID 10652267.
24. ^ Aranda A, Pascual A. Nuclear hormone receptors and gene expression [abstract]. Physiol. Rev.. 2001;81(3):1269–304. PMID 11427696.
25. ^ Brzozowski AM, Pike AC, Dauter Z, Hubbard RE, Bonn T, Engström O, Öhman L, Greene GL, Gustafsson J-Å, Carlquist M. Molecular basis of agonism and antagonism in the oestrogen receptor. Nature. 1997;389(6652):753–8. doi:10.1038/39645. PMID 9338790.
26. ^ Shiau AK, Barstad D, Loria PM, Cheng L, Kushner PJ, Agard DA, Greene GL. The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen. Cell. 1998;95(7):927–37. doi:10.1016/S0092-8674(00)81717-1. PMID 9875847.
27. ^ Gronemeyer H, Gustafsson JA, Laudet V. Principles for modulation of the nuclear receptor superfamily. Nature reviews. Drug discovery. 2004;3(11):950–64. doi:10.1038/nrd1551. PMID 15520817.
28. ^ Busch BB, Stevens WC, Martin R, et al.. Identification of a selective inverse agonist for the orphan nuclear receptor estrogen-related receptor alpha. J. Med. Chem.. 2004;47(23):5593–6. doi:10.1021/jm049334f. PMID 15509154.
29. ^ Smith CL, O'Malley BW. Coregulator function: a key to understanding tissue specificity of selective receptor modulators. Endocr Rev. 2004;25(1):45–71. doi:10.1210/er.2003-0023. PMID 14769827.
30. ^ Pascual G, Glass CK. Nuclear receptors versus inflammation: mechanisms of transrepression. Trends Endocrinol Metab. 2006;17(8):321–7. doi:10.1016/j.tem.2006.08.005. PMID 16942889.
31. ^ Björnström L, Sjöberg M. Estrogen receptor-dependent activation of AP-1 via non-genomic signalling. Nucl Recept. 2004;2(1):3. doi:10.1186/1478-1336-2-3. PMID 15196329.
32. ^ Zivadinovic D, Gametchu B, Watson CS. Membrane estrogen receptor-alpha levels in MCF-7 breast cancer cells predict cAMP and proliferation responses. Breast Cancer Res.. 2005;7(1):R101–12. doi:10.1186/bcr958. PMID 15642158.
33. ^ Wu W, Niles EG, El-Sayed N, Berriman M, LoVerde PT. Schistosoma mansoni (Platyhelminthes, Trematoda) nuclear receptors: sixteen new members and a novel subfamily. Gene. 2006;366(2):303–15. doi:10.1016/j.gene.2005.09.013. PMID 16406405.
34. ^ Wu W, Niles EG, Hirai H, LoVerde PT. Evolution of a novel subfamily of nuclear receptors with members that each contain two DNA binding domains. BMC Evol Biol. 2007;7(Feb 23):27. doi:10.1186/1471-2148-7-27. PMID 17319953.
35. ^ Tata JR. One hundred years of hormones. EMBO Rep.. 2005;6(6):490–6. doi:10.1038/sj.embor.7400444. PMID 15940278.

External links

• Eukaryotic Linear Motif resource motif class LIG_CORNRBOX
• Eukaryotic Linear Motif resource motif class LIG_NRBOX
• MeSH Nuclear+Receptors
• Vincent Laudet. The International Union of Basic and Clinical Pharmacology. The IUPHAR Compendium of the Pharmacology and Classification of the Nuclear Receptor Superfamily 2006E; 2006 [cited 2008-02-21].
• published by BioMed Central (no longer accepting submissions since May 2007). Nuclear Receptor online journal [cited 2008-02-21].
• Georgetown University. Nuclear Receptor Resource [cited 2008-02-21].
• The NURSA Consortium. Nuclear Receptor Signaling Atlas (Receptors, Coactivators, Corepressors and Ligands) [cited 2008-02-21]. "an NIH-funded research consortium and database; includes open-access PubMed-indexed journal, Nuclear Receptor Signaling"
• Jack Vanden Heuvel. Nuclear Receptor Resource [cited 2009-09-21].