View source for Nuclear receptor

{{Short description|Protein}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
[[Image:PPARg RXRa 3E00.png|thumb|325px|[[X-ray crystallography#Biological macromolecular crystallography|Crystallographic structure]] of a heterodimer of the nuclear receptors [[Peroxisome proliferator-activated receptor gamma|PPAR-γ]] (green) and [[Retinoid X receptor alpha|RXR-α]] (cyan) bound to double stranded [[DNA]] (magenta) and two molecules of the [[Nuclear receptor coactivator 2|NCOA2]] coactivator (red). The PPAR-γ antagonist GW9662 and RXR-α agonist [[retinoic acid]] are depicted as [[space-filling model]]s (carbon = white, oxygen = red, nitrogen = blue, chlorine = green).<ref name="Chandra_2008"/>]]

In the field of [[molecular biology]], '''nuclear receptors''' are a class of [[protein]]s responsible for sensing [[steroid hormone|steroids]], [[thyroid hormone|thyroid]] [[hormone]]s, [[vitamins]], and certain other molecules. These intracellular [[receptor (biochemistry)|receptors]] work with other proteins to regulate the [[gene expression|expression]] of specific [[gene]]s, thereby controlling the [[developmental biology|development]], [[Homeostasis#Overview|homeostasis]], and [[metabolism#Regulation and control|metabolism]] of the organism.

Nuclear receptors bind directly to [[DNA]] regulating the expression of adjacent genes; hence these receptors are classified as [[transcription factor]]s.<ref name="Evans_1988"/><ref name="Olefsky_2001"/> The regulation of gene expression by nuclear receptors often occurs in the presence of a [[ligand (biochemistry)|ligand]]—a molecule that affects the receptor's behavior. Ligand binding to a nuclear receptor results in a [[Conformational isomerism|conformational]] change activating the receptor. The result is [[Regulation of gene expression#Up-regulation and down-regulation|up- or down-regulation]] of gene expression.

A unique property of nuclear receptors that differentiates them from other classes of receptors is their direct control of [[genomic]] DNA. Nuclear receptors play key roles in both embryonic development and adult homeostasis. As discussed below, nuclear receptors are classified according to [[Nuclear receptor#Mechanism of action|mechanism]]<ref name="Mangelsdorf_1995"/><ref name="Novac_2004"/> or [[Nuclear receptor#Family members|homology]].<ref name="NRNC_1999"/><ref name="Laudet_1997"/>

== Species distribution ==
Nuclear receptors are specific to [[animal|metazoan]]s (animals) and are not found in [[protist]]s, [[algae]], [[fungi]], or plants.<ref name="Escriva_1998"/> Amongst the early-branching animal lineages with sequenced genomes, two have been reported from the [[sponge]] ''[[Amphimedon queenslandica]]'', two from the [[ctenophore|comb jelly]] ''[[Mnemiopsis leidyi]]''<ref name="Reitzel_2011"/> four from the [[placozoa]]n ''[[Trichoplax adhaerens]]'' and 17 from the [[cnidarian]] ''[[Nematostella vectensis]]''.<ref name="Bridgham_2010"/> There are 270 nuclear receptors in the [[nematode|roundworm]] ''[[Caenorhabditis elegans]]'' alone,<ref name="Sluder_2001"/> 21 in the [[Drosophila melanogaster|fruit fly]] and other insects,<ref name="Cheatle Jarvela_2017">{{cite journal|doi=10.1016/bs.ctdb.2017.01.003 | pmid=28527580 | title=The Function and Evolution of Nuclear Receptors in Insect Embryonic Development | year=2017 | journal=Current Topics in Developmental Biology | volume=125 | pages=39–70 | vauthors=Cheatle Jarvela AM, Pick L| isbn=9780128021729 }}</ref> 73 in [[zebrafish]].<ref name="Schaaf_2017">{{cite journal|doi=10.1530/JME-17-0031 | pmid=28438785 | volume=59 | title=Nuclear receptor research in zebrafish | year=2017 | journal=Journal of Molecular Endocrinology | pages=R65–R76 | vauthors=Schaaf MJ| issue=1 | doi-access=free }}</ref> Humans, mice, and rats have respectively 48, 49, and 47 nuclear receptors each.<ref name="Zhang_2004"/>

== Ligands ==
 [[Image:NR ligands.png|thumb|475px|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 [[lipophilicity|lipophilic]] substances such as [[endogenous]] [[hormone]]s, [[Vitamin A|vitamins A]] and [[Vitamin D|D]], and [[xenobiotic]] [[hormone]]s. 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 [[Food and Drug Administration (United States)|U.S. Food and Drug Administration]] (FDA) approved drugs target nuclear receptors.<ref name="Overington_2006"/>

A number of nuclear receptors, referred to as [[orphan receptor]]s,<ref name="Benoit_2006"/> have no known (or at least generally agreed upon) endogenous ligands. Some of these receptors such as [[Farnesoid X receptor|FXR]], [[Liver X receptor|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 [[constitutive androstane receptor|CAR]] and [[Pregnane X receptor|PXR]] appear to function as xenobiotic sensors up-regulating the expression of [[cytochrome P450]] enzymes that metabolize these xenobiotics.<ref name="Mohan_2003"/>
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== Structure ==
Most nuclear receptors have [[molecular mass]]es between 50,000 and 100,000 [[atomic mass unit|daltons]].

Nuclear receptors are modular in structure and contain the following [[structural domain|domains]]:<ref name="Kumar_1999"/><ref name="Klinge_2000"/>
* '''(A-B)''' [[N-terminus|N-terminal]] regulatory domain: Contains the activation function 1 ('''AF-1''') whose action is independent of the presence of ligand.<ref name="Wärnmark_2003"/> 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 finger]]s that binds to specific sequences of DNA called [[hormone response element]]s (HRE). Recently, a novel zinc finger motif (CHC2) is identified in parasitic flatworm NRs. <ref name="Wu_2021"/>
* '''(D)''' Hinge region: Thought to be a flexible domain that connects the DBD with the LBD. Influences intracellular trafficking and subcellular distribution with a [[target peptide]] sequence.{{Citation needed|date=April 2025|reason=The article cited, 'The structure of the nuclear hormone receptors', does not ever discuss a 'hinge domain'}}
* '''(E)''' Ligand binding domain ('''LBD'''): Moderately conserved in sequence and highly conserved in structure between the various nuclear receptors. The [[tertiary structure|structure]] of the LBD is referred to as an [[alpha helix|alpha helical]] sandwich [[protein folding|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 [[Coactivation (Transcription)|coactivator]] and [[Corepressor (genetics)|corepressor]] proteins. The LBD also contains the activation function 2 ('''AF-2''') whose action is dependent on the presence of bound ligand, controlled by the conformation of helix 12 (H12).<ref name="Wärnmark_2003" />
* '''(F)''' [[C-terminus|C-terminal]] domain: Highly variable in sequence between various nuclear receptors.

The DNA-binding (C), and ligand binding (E) domains are independently well folded and structurally stable while the N-terminal (A/B), hinge region (D) and optional C-terminal (F) domains may be conformationally flexible and disordered.<ref name="Weatherman_1999"/> Domains relative orientations are very different by comparing three known multi-domain crystal structures, two of them binding on DR1 (DBDs separated by 1 bp),<ref name="Chandra_2008"/><ref name="Chandra_2013"/> one binding on DR4 (by 4 bp).<ref name="pmid24561505">{{cite journal | vauthors = Lou X, Toresson G, Benod C, Suh JH, Philips KJ, Webb P, Gustafsson JA | title = Structure of the retinoid X receptor α-liver X receptor β (RXRα-LXRβ) heterodimer on DNA | journal = Nature Structural & Molecular Biology | volume = 21 | issue = 3 | pages = 277–81 | date = March 2014 | pmid = 24561505 | doi = 10.1038/nsmb.2778 | s2cid = 23226682 }}</ref>

{|
|- valign=top
|[[Image:Nuclear Receptor Structure.png|thumb|415px|'''Structural Organization of Nuclear Receptors'''<br />'''Top''' – Schematic 1D [[peptide sequence|amino acid sequence]] of a nuclear receptor.<br />'''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.]]
|{{Pfam_box
| Symbol = zf-C4
| Name = DNA binding domain (DBD)
| image =  PR_DBD_2C7A.png
| width =
| caption = [[X-ray crystallography#Biological macromolecular crystallography|Crystallographic structure]] of the human [[progesterone receptor]] DNA-binding domain dimer (cyan and green) complexed with double stranded DNA (magenta).  Zinc atoms of are depicted as grey spheres.<ref name="Roemer_2006"/>
| Pfam = PF00105
| InterPro = IPR001628
| SMART = SM00399
| PROSITE = PDOC00031
| SCOP = 1hra
| TCDB =
| OPM family =
| OPM protein =
| CDD = cd06916
}}
|{{Pfam_box
| Symbol = Hormone_recep
| Name = Ligand-binding domain (LBD)
| image = RORC_3L0L.png
| width =
| caption = [[X-ray crystallography#Biological macromolecular crystallography|Crystallographic structure]] of the ligand binding domain of the human [[RAR-related orphan receptor gamma|RORγ]] (rainbow colored, [[N-terminus]] = blue, [[C-terminus]] = red) complexed with 25-hydroxycholesterol ([[space-filling model]] (carbon = white, oxygen = red) and the [[Nuclear receptor coactivator 2|NCOA2]] coactivator (magneta).<ref name="Jin_2010"/>
| Pfam = PF00104
| InterPro = IPR000536
| SMART = SM00430
| PROSITE =
| SCOP = 1lbd
| TCDB =
| OPM family =
| OPM protein =
| CDD = cd06157
}}
|}
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== Mechanism of action ==
[[Image:Nuclear receptor action.png|thumb|475px|'''Mechanism of class I nuclear receptor action'''. A class I nuclear receptor (NR), in the absence of [[ligand (biochemistry)|ligand]], is located in the [[cytosol]]. Hormone binding to the NR triggers dissociation of heat shock proteins ([[heat shock protein|HSP]]), dimerization, and [[protein targeting|translocation]] to the nucleus, where the NR binds to a specific sequence of [[DNA]] known as a hormone response element ([[hormone response element|HRE]]). The nuclear receptor DNA complex in turn recruits other [[protein]]s that are responsible for [[transcription (genetics)|transcription]] of downstream DNA into [[messenger RNA|mRNA]], which is eventually translated into protein, which results in a change in cell function.]]
[[Image:Type ii nuclear receptor action.png|thumb|475px|'''Mechanism of class II nuclear receptor action'''. A class II nuclear receptor (NR), 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 ([[thyroid hormone receptor|TR]]) heterodimerized to the [[Retinoid X receptor|RXR]]. In the absence of ligand, the TR is bound to [[corepressor (genetics)|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.]]

Nuclear receptors are multifunctional proteins that [[signal transduction|transduce signals]] of their cognate [[ligand (biochemistry)|ligands]]. Nuclear receptors (NRs) may be classified into two broad classes according to their mechanism of action and subcellular distribution in the absence of ligand.{{cn|date=December 2024}}

Small lipophilic substances such as natural hormones diffuse through the cell membrane and bind to nuclear receptors located in the cytosol (type I NR) or nucleus (type II NR) of the cell. Binding causes a conformational change in the receptor which, depending on the class of receptor, triggers a cascade of downstream events that direct the NRs to DNA transcription regulation sites which result in up or down-regulation of gene expression. They generally function as homo/heterodimers.<ref name="Amoutzias_2007">{{cite journal | vauthors = Amoutzias GD, Pichler EE, Mian N, De Graaf D, Imsiridou A, Robinson-Rechavi M, Bornberg-Bauer E, Robertson DL, Oliver SG | title = A protein interaction atlas for the nuclear receptors: properties and quality of a hub-based dimerisation network | journal = BMC Systems Biology | volume = 1 | pages = 34 | date = July 2007 | pmid = 17672894 | pmc = 1971058 | doi = 10.1186/1752-0509-1-34 | doi-access = free }}</ref> 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 identified.<ref name="Mangelsdorf_1995"/>

Accordingly, nuclear receptors may be subdivided into the following four mechanistic classes:<ref name="Mangelsdorf_1995"/><ref name="Novac_2004"/>

===Type I===
Ligand binding to type I nuclear receptors in the cytosol results in the [[Dissociation (chemistry)|dissociation]] of [[heat shock protein]]s, homo-[[protein dimerization|dimerization]], translocation (''i.e.'', [[active transport]]) from the [[cytoplasm]] into the [[cell nucleus]], and binding to specific sequences of [[DNA]] known as [[hormone response element]]s (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 receptor]]s, [[glucocorticoid receptor]], and [[progesterone receptor]].<ref name="Linja_2004"/>

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. These nuclear receptors are considered [[orphan receptor]]s, as their endogenous ligands are still unknown.{{cn|date=December 2024}}

The nuclear receptor/DNA [[complex (chemistry)|complex]] then recruits other proteins that [[Transcription (genetics)|transcribe]] DNA downstream from the HRE into [[messenger RNA]] and eventually [[protein]], which causes a change in cell function.{{cn|date=December 2024}}

===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 [[Retinoid X receptor|RXR]]) to DNA.<ref name="Amoutzias_2007" /> In the absence of ligand, type II nuclear receptors are often complexed with [[Corepressor (genetics)|corepressor]] proteins. Ligand binding to the nuclear receptor causes dissociation of corepressor and recruitment of [[coactivation (Transcription)|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]].<ref name="Klinge_1997"/>

===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.

== Dimerization ==
Human nuclear receptors are capable of dimerizing with many other nuclear receptors (homotypic dimerization), as has been shown from large-scale Y2H experiments and text mining efforts of the literature that were focused on specific interactions.<ref>{{cite journal | vauthors = Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M | title = Towards a proteome-scale map of the human protein-protein interaction network | journal = Nature | volume = 437 | issue = 7062 | pages = 1173–1178 | date = October 2005 | pmid = 16189514 | doi = 10.1038/nature04209 | s2cid = 4427026 | bibcode = 2005Natur.437.1173R }}</ref><ref>{{cite journal | vauthors = Albers M, Kranz H, Kober I, Kaiser C, Klink M, Suckow J, Kern R, Koegl M | title = Automated yeast two-hybrid screening for nuclear receptor-interacting proteins | journal = Molecular & Cellular Proteomics | volume = 4 | issue = 2 | pages = 205–213 | date = February 2005 | pmid = 15604093 | doi = 10.1074/mcp.M400169-MCP200 | s2cid = 14876486 | doi-access = free }}</ref><ref name="Amoutzias_2007" /> Nevertheless, there exists specificity, with members of the same subfamily having very similar NR dimerization partners and the underlying dimerization network has certain topological features, such as the presence of highly connected hubs (RXR and SHP).<ref name="Amoutzias_2007" />

== Coregulatory proteins ==
{{main|nuclear receptor coregulators}}

Nuclear receptors bound to hormone response elements recruit a significant number of other proteins (referred to as [[transcription coregulator]]s) that facilitate or inhibit the transcription of the associated target gene into mRNA.<ref name="McKenna_1999"/><ref name="Glass_2000"/><ref name="Aranda_2001"/> 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. Nuclear receptors may bind specifically to a number of coregulator proteins, and thereby influence cellular mechanisms of signal transduction both directly, as well as indirectly.<ref name="pmid19382224">{{cite journal | vauthors = Copland JA, Sheffield-Moore M, Koldzic-Zivanovic N, Gentry S, Lamprou G, Tzortzatou-Stathopoulou F, Zoumpourlis V, Urban RJ, Vlahopoulos SA | title = Sex steroid receptors in skeletal differentiation and epithelial neoplasia: is tissue-specific intervention possible? | journal = BioEssays | volume = 31 | issue = 6 | pages = 629–41 | date = June 2009 | pmid = 19382224 | doi = 10.1002/bies.200800138 | s2cid = 205469320 }}</ref>

=== Coactivators ===
Binding of agonist ligands (see section below) to nuclear receptors induces a conformation of the receptor that preferentially binds [[coactivator (genetics)|coactivator]] proteins. These proteins often have an intrinsic [[histone acetyltransferase]] (HAT) activity, which weakens the association of [[histone]]s 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 (genetics)|corepressor]] proteins. These proteins, in turn, recruit [[histone deacetylase]]s (HDACs), which strengthens the association of histones to DNA, and therefore represses gene transcription.

== Agonism vs antagonism ==
[[Image:NR mechanism.png|thumb|480px|'''Structural basis for the mechanism of nuclear receptor agonist and antagonist action.'''<ref name="Brzozowski_1997"/> 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, {{PDB2|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 (genetics)|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.<ref name="Shiau_1998"/> Antagonists occupy the same ligand binding cavity of the nuclear receptor. However antagonist ligands in addition have a sidechain extension which [[steric effects|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.<ref name="Gronemeyer_2004"/>

=== 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 receptor|glucocorticoid]] and [[progesterone receptor|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 binding, 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 agonist]]s.<ref name="Busch_2004"/>

=== 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 ([[selective androgen receptor modulators|SARM]]s), Selective Estrogen Receptor Modulators ([[selective estrogen receptor modulator|SERM]]s) and Selective Progesterone Receptor Modulators ([[selective progesterone receptor modulator|SPRM]]s). 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 (genetics)|coactivator]] proteins is higher than [[corepressor (genetics)|corepressors]], the equilibrium is shifted in the agonist direction. Conversely in tissues where [[corepressor (genetics)|corepressors]] dominate, the ligand behaves as an antagonist.<ref name="Smith_2004"/>

== Alternative mechanisms ==
[[Image:Nr alignment tree.jpg|thumb|480px|'''[[Phylogenetics|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]]'''.<ref name="Pascual_2006"/> 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 ([[Selective glucocorticoid receptor agonist|SEGRA]]s) 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 [[glucocorticoid]]s.

=== Non-genomic ===
The classical direct effects of nuclear receptors on gene regulation normally take 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 many effects of the application of nuclear hormones, such as changes in ion channel activity, 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.<ref name="Björnström_2004"/><ref name="Zivadinovic_2005"/>

While it has been hypothesized that there are several membrane associated receptors for nuclear hormones, many of the rapid effects have been shown to require canonical nuclear receptors.<ref name="Kousteni_2001"/><ref name="Storey_2006"/> However, testing the relative importance of the genomic and nongenomic mechanisms in vivo has been prevented by the absence of specific molecular mechanisms for the nongenomic effects that could be blocked by mutation of the receptor without disrupting its direct effects on gene expression.

A molecular mechanism for non-genomic signaling through the nuclear thyroid hormone receptor [[thyroid hormone receptor beta|TRβ]] involves the phosphatidylinositol 3-kinase ([[PI3K]]).<ref name="Storey_2002"/> This signaling can be blocked by a single [[tyrosine]] to [[phenylalanine]] substitution in TRβ without disrupting direct gene regulation.<ref name="Martin_2014"/> When mice were created with this single, conservative amino acid substitution in TRβ,<ref name="Martin_2014"/> [[synapse|synaptic]] maturation and plasticity in the [[hippocampus]] was impaired almost as effectively as completely blocking thyroid hormone synthesis.<ref name="Gilbert_2004"/> This mechanism appears to be conserved in all mammals but not in [[Thyroid hormone receptor alpha|TRα]] or any other nuclear receptors. Thus, phosphotyrosine-dependent association of TRβ with PI3K provides a potential mechanism for integrating regulation of development and metabolism by thyroid hormone and receptor tyrosine kinases. In addition, thyroid hormone signaling through PI3K can alter gene expression.<ref name="Moeller_2011"/>

== Family members ==
The following is a list of the 48 known human nuclear receptors (and their [[ortholog]]s in other species)<ref name="Zhang_2004"/><ref name="Kaur2015"/><ref>{{Cite journal |vauthors=Burris TP, de Vera IM, Cote I, Flaveny CA, Wanninayake US, Chatterjee A, Walker JK, Steinauer N, Zhang J, Coons LA, Korach KS, Cain DW, Hollenberg AN, Webb P, Forrest D, Jetten AM, Edwards DP, Grimm SL, Hartig S, Lange CA, Richer JK, Sartorius CA, Tetel M, Billon C, Elgendy B, Hegazy L, Griffett K, Peinetti N, Burnstein KL, Hughes TS, Sitaula S, Stayrook KR, Culver A, Murray MH, Finck BN, Cidlowski JA |date=November 2023 | veditors = Ohlstein E |title=International Union of Basic and Clinical Pharmacology CXIII: Nuclear Receptor Superfamily—Update 2023 |journal=[[Pharmacological Reviews]] |language=en |volume=75 |issue=6 |pages=1233–1318 |doi=10.1124/pharmrev.121.000436 |issn=0031-6997 |pmc=10595025 |pmid=37586884}}</ref> categorized according to [[sequence homology]].<ref name="NRNC_1999"/><ref name="Laudet_1997"/> The list also includes selected family members that lack human orthologs (NRNC symbol highlighted in yellow).

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{| class="wikitable" style="text-align: center; "
|-
! colspan="2" rowspan="2"  | Subfamily
! colspan="2" rowspan="2"  | Group
! colspan="5" |  Member
|-
! NRNC Symbol<ref name="NRNC_1999"/>
! Abbreviation
! Name
! Gene
! Ligand(s)
<!-- We only need to specify the width once, right here. -->
|- style="background: #CCEEEE;"
| rowspan="27" style="width: 25px"  | '''1'''
| rowspan="27" style="width: 300px" | Thyroid Hormone Receptor-like
| rowspan="2" style="width: 25px;  background: #CCEEEE"  | '''A'''
| rowspan="2" style="width: 300px;  background: #CCEEEE" | [[Thyroid hormone receptor]]
| style="width: 100px;" | NR1A1
| style="width: 100px;" | [[thyroid hormone receptor alpha|TRα]]
| style="width: 350px;" | Thyroid hormone receptor-α
| style="width: 50px;" | {{Gene|THRA}}
| rowspan="2"  style="width: 250px"  | [[thyroid hormone]]
|- style="background: #CCEEEE;"
| NR1A2
|  [[thyroid hormone receptor beta|TRβ]]
| Thyroid hormone receptor-β
| {{Gene|THRB}}
|-
| rowspan="3" | '''B'''
| rowspan="3" | [[Retinoic acid receptor]]
| NR1B1
| [[retinoic acid receptor alpha|RARα]]
| Retinoic acid receptor-α
| {{Gene|RARA}}
| rowspan="3" align="center"| [[vitamin A]] and related compounds
|-
| align="center" | NR1B2
| [[retinoic acid receptor beta|RARβ]]
| Retinoic acid receptor-β
| {{Gene|RARB}}
|-
| NR1B3
| [[retinoic acid receptor gamma|RARγ]]
| Retinoic acid receptor-γ
| {{Gene|RARG}}
|- style="background: #CCEEEE;" |
| rowspan="3" | '''C'''
| rowspan="3" | [[Peroxisome proliferator-activated receptor]]
| align="center" | NR1C1
| [[peroxisome proliferator-activated receptor alpha|PPARα]]
| Peroxisome proliferator-activated receptor-α
| {{Gene|PPARA}}
| rowspan="3" align="center" | [[fatty acids]], [[prostaglandin]]s
|- style="background: #CCEEEE;"
| NR1C2
| [[peroxisome proliferator-activated receptor delta|PPAR-β/δ]]
| Peroxisome proliferator-activated receptor-β/δ
| {{Gene|PPARD}}
|- style="background: #CCEEEE;"
| NR1C3
| [[peroxisome proliferator-activated receptor gamma|PPARγ]]
| Peroxisome proliferator-activated receptor-γ
| {{Gene|PPARG}}
|-
| rowspan="2" | '''D'''
| rowspan="2" | [[Rev-ErbA]]
| NR1D1
| [[Rev-ErbA alpha|Rev-ErbAα]]
| Rev-ErbAα
| {{Gene|NR1D1}}
| rowspan="2" | [[heme]]
|-
| NR1D2
| [[Rev-ErbA beta|Rev-ErbAβ]]
| Rev-ErbAα
| {{Gene|NR1D2}}
|-style="background: #CCEEEE;"
|'''E'''
|E78C-like<br /><small>(arthropod, trematode, mullosc, nematode)</small><ref name="Kaur2015"/><ref name="E78-nematoda">{{cite journal | vauthors = Crossgrove K, Laudet V, Maina CV | title = Dirofilaria immitis encodes Di-nhr-7, a putative orthologue of the Drosophila ecdysone-regulated E78 gene | journal = Molecular and Biochemical Parasitology | volume = 119 | issue = 2 | pages = 169–77 | date = February 2002 | pmid = 11814569 | doi = 10.1016/s0166-6851(01)00412-1 }}</ref>
|style="background: #FFF8DC;" |NR1E1
|Eip78C
|Ecdysone-induced protein 78C
|[https://www.uniprot.org/uniprot/P45447 ''Eip78C'']
|
|-
| rowspan="3"   | '''F'''
| rowspan="3" | [[RAR-related orphan receptor]]
| align="center" | NR1F1
|[[RAR-related orphan receptor alpha|RORα]]
| RAR-related orphan receptor-α
| {{Gene|RORA}}
| rowspan="3"  | [[cholesterol]], [[tretinoin|ATRA]]
|-
| NR1F2
| [[RAR-related orphan receptor beta|RORβ]]
| RAR-related orphan receptor-β
| {{Gene|RORB}}
|-
| NR1F3
| [[RAR-related orphan receptor gamma|RORγ]]
| RAR-related orphan receptor-γ
| {{Gene|RORC}}
|- style="background: #CCEEEE;"
|'''G'''
|CNR14-like <small>(nematode)</small><ref name="Kaur2015"/>
|style="background: #FFF8DC;" |NR1G1
|sex-1
|Steroid hormone receptor cnr14<ref name="wb-sex-1">{{cite web |title=sex-1 (gene) |url=https://www.wormbase.org/species/c_elegans/gene/WBGene00004786 |website=WormBase : Nematode Information Resource}}</ref>
|[https://www.uniprot.org/uniprot/P41830 ''sex-1'']
|
|-
| rowspan="5" | '''H'''
| rowspan="5" | [[Liver X receptor]]-like
|style="background: #FFF8DC;" | NR1H1
| [[Ecdysone receptor|EcR]]
| Ecdysone receptor, EcR (arthropod)
| [https://www.uniprot.org/uniprot/P34021 ''EcR'']
| [[ecdysteroids]]
|-
| NR1H2
| [[liver X receptor beta|LXRβ]]
| Liver X receptor-β
| {{Gene|NR1H2}}
| rowspan="4" | [[oxysterol]]s
|-
| NR1H3
| [[liver X receptor alpha|LXRα]]
| Liver X receptor-α
| {{Gene|NR1H3}}
|-
| NR1H4
| [[Farnesoid X receptor|FXR]]
| Farnesoid X receptor
| {{Gene|NR1H4}}
|-
|style="background: #FFF8DC;" | NR1H5<ref name="pmid12529392">{{cite journal | vauthors = Otte K, Kranz H, Kober I, Thompson P, Hoefer M, Haubold B, Remmel B, Voss H, Kaiser C, Albers M, Cheruvallath Z, Jackson D, Casari G, Koegl M, Pääbo S, Mous J, Kremoser C, Deuschle U | title = Identification of farnesoid X receptor beta as a novel mammalian nuclear receptor sensing lanosterol | journal = Molecular and Cellular Biology | volume = 23 | issue = 3 | pages = 864–72 | date = February 2003 | pmid = 12529392 | pmc = 140718 | doi = 10.1128/mcb.23.3.864-872.2003 }}</ref>
| [[Farnesoid X receptor beta|FXR-β]]
| Farnesoid X receptor-β<br /><small>(pseudogene in human)</small>
| {{Gene|NR1H5P}}
|-style="background: #CCEEEE;"
| rowspan="3" | '''I'''
| rowspan="3" | Vitamin D receptor-like
| NR1I1
| [[Vitamin D receptor|VDR]]
| Vitamin D receptor
| {{Gene|VDR}}
| [[vitamin D]]
|- style="background: #CCEEEE;"
| NR1I2
| [[Pregnane X receptor|PXR]]
| Pregnane X receptor
| {{Gene|NR1I2}}
| [[xenobiotic]]s
|- style="background: #CCEEEE;"
| NR1I3
| [[Constitutive androstane receptor|CAR]]
| Constitutive androstane receptor
| {{Gene|NR1I3}}
| [[androstane]]
|-
| rowspan="3" | '''J'''
| rowspan="3" | Hr96-like<ref name="Kaur2015"/>
|style="background: #FFF8DC;" |NR1J1
|Hr96/[[Daf-12]]
|Nuclear hormone receptor HR96
| [https://www.uniprot.org/uniprot/Q24143 ''Hr96'']
| [[cholesterol]]/[[dafachronic acid]]<ref>{{cite web |title=FlyBase Gene Report: Dmel\Hr96 |url=http://flybase.org/reports/FBgn0015240.html |website=FlyBase |access-date=14 August 2019}}</ref>
|-
|style="background: #FFF8DC;" |NR1J2
|
|
|
|
|-
|style="background: #FFF8DC;" |NR1J3
|
|
|
|
|-
| rowspan="1" | '''K'''
| rowspan="1" | Hr1-like<ref name="Kaur2015"/>
|style="background: #FFF8DC;" |NR1K1
|Hr1
|Nuclear hormone receptor HR1
|
|
|-style="background: #CCEECC"
| rowspan="13"  | '''2'''
| rowspan="13"| Retinoid X Receptor-like
| rowspan="2"  | '''A'''
| rowspan="2"| [[Hnf4|Hepatocyte nuclear factor-4]]
| NR2A1
| [[hepatocyte nuclear factor 4 alpha|HNF4α]]
| Hepatocyte nuclear factor-4-α
| {{Gene|HNF4A}}
| rowspan="2"   | [[fatty acid]]s
|-  style="background: #CCEECC;"
| align="center" | NR2A2
| [[hepatocyte nuclear factor 4 gamma|HNF4γ]]
| Hepatocyte nuclear factor-4-γ
| {{Gene|HNF4G}}
|-
| rowspan="4" | '''B'''
| rowspan="4" |  [[Retinoid X receptor]]
| NR2B1
| [[retinoid X receptor alpha|RXRα]]
| Retinoid X receptor-α
| {{Gene|RXRA}}
| rowspan="3" | [[retinoid]]s
|-
| align="center" | NR2B2
| [[retinoid X receptor beta|RXRβ]]
| Retinoid X receptor-β
| {{Gene|RXRB}}
|-
| align="center" | NR2B3
| [[retinoid X receptor gamma|RXRγ]]
| Retinoid X receptor-γ
| {{Gene|RXRG}}
|-
|style="background: #FFF8DC;" | NR2B4
| [[Ultraspiracle protein|USP]]
| Ultraspiracle protein (arthropod)
| [https://www.uniprot.org/uniprot/P20153 ''usp'']
| phospholipids<ref name=Schewabe04/>
|- style="background: #CCEECC"
| rowspan="2" | '''C'''
| rowspan="2" | [[Testicular receptor]]
| NR2C1
| [[testicular receptor 2|TR2]]
| Testicular receptor 2
| {{Gene|NR2C1}}
| rowspan="2"|
|-  style="background: #CCEECC;"
| align="center" | NR2C2
| [[testicular receptor 4|TR4]]
| Testicular receptor 4
| {{Gene|NR2C2}}
|-
| rowspan="2" | '''E'''
| rowspan="2" | TLX/PNR
| NR2E1
| [[TLX]]
| Homologue of the Drosophila tailless gene
| {{Gene|NR2E1}}
| rowspan="2" |
|-
| NR2E3
| [[Photoreceptor cell-specific nuclear receptor|PNR]]
| Photoreceptor cell-specific nuclear receptor
| {{Gene|NR2E3}}
|-style="background: #CCEECC"
| rowspan="3"| '''F'''
| rowspan="3"|  [[Chicken ovalbumin upstream promoter-transcription factor|COUP]]/EAR
| NR2F1
| [[COUP-TFI]]
| Chicken ovalbumin upstream promoter-transcription factor I
| {{Gene|NR2F1}}
|
|- style="background: #CCEECC"
| NR2F2
| [[COUP-TFII]]
| Chicken ovalbumin upstream promoter-transcription factor II
| {{Gene|NR2F2}}
| [[retinoic acid]] (weak)<ref name="pmid18798693">{{cite journal | vauthors = Kruse SW, Suino-Powell K, Zhou XE, Kretschman JE, Reynolds R, Vonrhein C, Xu Y, Wang L, Tsai SY, Tsai MJ, Xu HE | title = Identification of COUP-TFII orphan nuclear receptor as a retinoic acid-activated receptor | journal = PLOS Biology | volume = 6 | issue = 9 | pages = e227 | date = September 2008 | pmid = 18798693 | pmc = 2535662 | doi = 10.1371/journal.pbio.0060227 | doi-access = free }}</ref>
|- style="background: #CCEECC"
| NR2F6
| [[V-erbA-related gene|EAR-2]]
|  V-erbA-related gene|V-erbA-related
| {{Gene|NR2F6}}
|
|-style="background: #CCEEEE;"
| rowspan="12" | '''3'''
| rowspan="12" | Estrogen Receptor-like
| rowspan="2" | '''A'''
| rowspan="2" |  [[Estrogen receptor]]
| NR3A1
| [[estrogen receptor alpha|ERα]]
| Estrogen receptor-α
| {{Gene|ESR1}}
| rowspan="2" | [[estrogen]]s
|- style="background: #CCEEEE;"
| align="center" | NR3A2
| [[estrogen receptor beta|ERβ]]
| Estrogen receptor-β
| {{Gene|ESR2}}
|-
| rowspan="3" | '''B'''
| rowspan="3" | [[Estrogen related receptor]]
| NR3B1
| [[estrogen-related receptor alpha|ERRα]]
| Estrogen-related receptor-α
| {{Gene|ESRRA}}
| rowspan="3" |
|-
| align="center" | NR3B2
| [[estrogen-related receptor beta|ERRβ]]
| Estrogen-related receptor-β
| {{Gene|ESRRB}}
|-
| align="center" | NR3B3
| [[estrogen-related receptor gamma|ERRγ]]
| Estrogen-related receptor-γ
| {{Gene|ESRRG}}
|-style="background: #CCEEEE;"
| rowspan="4" | '''C'''
| rowspan="4" | 3-Ketosteroid receptors
| NR3C1
| [[glucocorticoid receptor|GR]]
| Glucocorticoid receptor
| {{Gene|NR3C1}}
| [[cortisol]]
|- style="background: #CCEEEE;"
| align="center" | NR3C2
| [[mineralocorticoid receptor|MR]]
| Mineralocorticoid receptor
| {{Gene|NR3C2}}
| [[aldosterone]]
|- style="background: #CCEEEE;"
| align="center" | NR3C3
| [[progesterone receptor|PR]]
| Progesterone receptor
| {{Gene|PGR}}
| [[progesterone]]
|- style="background: #CCEEEE;"
| align="center" | NR3C4
| [[androgen receptor|AR]]
| Androgen receptor
| {{Gene|AR}}
| [[testosterone]]
|-
|  '''D'''
| Estrogen Receptor-like<br /><small>(in [[lophotrochozoa]])</small><ref name="Markov2017">{{cite journal | vauthors = Markov GV, Gutierrez-Mazariegos J, Pitrat D, Billas IM, Bonneton F, Moras D, Hasserodt J, Lecointre G, Laudet V | title = Origin of an ancient hormone/receptor couple revealed by resurrection of an ancestral estrogen | journal = Science Advances | volume = 3 | issue = 3 | pages = e1601778 | date = March 2017 | pmid = 28435861 | doi = 10.1126/sciadv.1601778 | pmc = 5375646 | bibcode = 2017SciA....3E1778M }}</ref>
| style="background: #FFF8DC;" | NR3D
|
|
|
|
|- style="background: #CCEEEE;"
|  '''E'''
| Estrogen Receptor-like<br /><small>(in [[cnidaria]])</small><ref name="Khalturin2018">{{cite journal | vauthors = Khalturin K, Billas I, Chebaro Y, Reitzel AM, Tarrant AM, Laudet V, Markov GV | title = NR3E receptors in cnidarians : a new family of steroid receptor relatives extends the possible mechanisms for ligand binding | journal = J Steroid Biochem Mol Biol | volume = 184 | pages = 11–19 | date = November 2018 | pmid = 29940311 | pmc = 6240368 | doi = 10.1016/j.jsbmb.2018.06.014 }}</ref>
| style="background: #FFF8DC;" | NR3E
|
|
|
|
|-
|  '''F'''
| Estrogen Receptor-like<br /><small>(in [[placozoa]])</small><ref name="Khalturin2018"/>
| style="background: #FFF8DC;" | NR3F
|
|
|
|
|-style="background: #CCEECC"
| rowspan="3"   | '''4'''
| rowspan="3" | Nerve Growth Factor IB-like
| rowspan="3" | '''A'''
| rowspan="3" |  NGFIB/NURR1/NOR1
| NR4A1
| [[Nerve Growth factor IB|NGFIB]]
| Nerve Growth factor IB
| {{Gene|NR4A1}}
| rowspan="3"  style="background: #CCEECC"  |
|- style="background: #CCEECC;"
| align="center" | NR4A2
| [[Nuclear receptor related 1 protein|NURR1]]
| Nuclear receptor related 1
| {{Gene|NR4A2}}
|- style="background: #CCEECC;"
| align="center" | NR4A3
| [[Neuron-derived orphan receptor 1|NOR1]]
| Neuron-derived orphan receptor 1
| {{Gene|NR4A3}}
|-style="background: #CCEEEE;"
| rowspan="3" | '''5'''
| rowspan="3" | Steroidogenic<br />Factor-like
| rowspan="2" | '''A'''
| rowspan="2" |  SF1/LRH1
| NR5A1
| [[Steroidogenic factor 1|SF1]]
| Steroidogenic factor 1
| {{Gene|NR5A1}}
| [[phosphatidylinositol]]s
|- style="background: #CCEEEE;"
| align="center" | NR5A2
| [[Liver receptor homolog-1|LRH-1]]
| Liver receptor homolog-1
| {{Gene|NR5A2}}
| [[phosphatidylinositol]]s
|-
|-
| '''B'''
| Hr39-like
|style="background: #FFF8DC;" | NR5B1<ref name="Kaur2015"/>
| HR39/[[FTZ-F1]]
| Nuclear hormone receptor fushi tarazu factor I beta
| [https://www.uniprot.org/uniprot/Q05192 ''Hr39'']
|
|- style="background: #CCEECC;"
| rowspan="1"   | '''6'''
| rowspan="1" | Germ Cell Nuclear Factor-like
| '''A'''
|  GCNF
| NR6A1
| [[Germ cell nuclear factor|GCNF]]
| Germ cell nuclear factor
| {{Gene|NR6A1}}
|
|-style="background: #CCEEEE;"
| rowspan="3"  | '''7'''
| rowspan="3" | NRs with two DNA binding domains<ref name="Wu2023">{{cite journal | vauthors = Wu, W, LoVerde PT | title = Updated knowledge and a proposed nomenclature for nuclear receptors with two DNA binding domains (2DBD-NRs) | journal = PLOS ONE | volume = 18 | issue = 9 | pages = e0286107 | date = September 2023 | pmid = 37699039 | pmc = 10497141 | doi = 10.1371/journal.pone.0286107 | bibcode = 2023PLoSO..1886107W | doi-access = free }}</ref><ref name="Kaur2015">{{cite journal | vauthors = Kaur S, Jobling S, Jones CS, Noble LR, Routledge EJ, Lockyer AE | title = The nuclear receptors of Biomphalaria glabrata and Lottia gigantea: implications for developing new model organisms | journal = PLOS ONE | volume = 10 | issue = 4 | pages = e0121259 | date = 7 April 2015 | pmid = 25849443 | pmc = 4388693 | doi = 10.1371/journal.pone.0121259 | doi-access = free | bibcode = 2015PLoSO..1021259K }}</ref><ref name="Wu2007">{{cite journal | vauthors = Wu W, Niles EG, Hirai H, LoVerde PT | title = Evolution of a novel subfamily of nuclear receptors with members that each contain two DNA binding domains | journal = BMC Evol Biol | volume = 7 | issue = 27 | date = February 2007 | page = 27 | pmid = 17319953 | pmc = 1810520 | doi = 10.1186/1471-2148-7-27 | doi-access = free | bibcode = 2007BMCEE...7...27W }}</ref>
| '''A''' || 2DBD-NRα
|style="background: #FFF8DC;"| NR7A1|| 2DBD-NRA2 || || ||
|-
| '''B''' || 2DBD-NRβ
|style="background: #FFF8DC;"| NR7B1 || 2DBD-NRA3 || || ||
|- style="background: #CCEEEE;"
| '''C''' || 2DBD-NRγ
|style="background: #FFF8DC;"| NR7C1 || 2DBD-NRA1 || arthropod "α/β" || ||
|-style="background: #CCEECC;"
| '''8'''
| NR8<ref name="pmid25956376">{{cite journal | vauthors = Huang W, Xu F, Li J, Li L, Que H, Zhang G | title = Evolution of a novel nuclear receptor subfamily with emphasis on the member from the Pacific oyster Crassostrea gigas | journal = Gene | volume = 567 | issue = 2 | pages = 164–72 | date = August 2015 | pmid = 25956376 | doi = 10.1016/j.gene.2015.04.082 }}</ref> <small>([[eumetazoa]])</small>
| '''A'''
| NR8A
|style="background: #FFF8DC;" | NR8A1
| CgNR8A1
| Nuclear receptor 8
| [https://www.ncbi.nlm.nih.gov/protein/818946855 AKG49571]
|
|- style="background: #CCEEEE;"
| rowspan="3"  | '''0'''
| rowspan="3" | Miscellaneous (lacks either LBD or DBD)
| '''A'''
| knr/knrl/egon<ref name="Kaur2015"/> <small>(arthropods)</small>
|style="background: #FFF8DC;" | NR0A1
| KNI
| Zygotic gap protein knirps
| [https://www.uniprot.org/uniprot/P10734 ''knl'']
|
|-
| rowspan="2"| '''B'''
| rowspan="2"  |  DAX/SHP
| NR0B1
| [[DAX1]]
| Dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1
| {{Gene|NR0B1}}
| rowspan="2"  |
|-
| align="center" | NR0B2
| [[Small heterodimer partner|SHP]]
| Small heterodimer partner
| {{Gene|NR0B2}}
|}

Of the two 0-families, 0A has a family 1-like DBD, and 0B has a unique LBD. The second DBD of family 7 is probably related to the family 1 DBD. Three probably family-1 NRs from ''[[Biomphalaria glabrata]]'' possess a DBD along with a family 0B-like LBD.<ref name="Kaur2015"/> The placement of ''[[C. elegans]]'' nhr-1 ({{UniProt|Q21878}}) is disputed: although most sources place it as NR1K1,<ref name="Kaur2015"/> manual annotation at [[WormBase]] considers it a member of NR2A.<ref>{{cite web |title=nhr-1 (gene) |url=https://www.wormbase.org/species/c_elegans/gene/WBGene00003600 |website=WormBase : Nematode Information Resource}}</ref> There used to be a group 2D for which the only member was ''[[Drosophila]]'' HR78/NR1D1 ({{UniProt|Q24142}}) and orthologues, but it was merged into group 2C later due to high similarity, forming a "group 2C/D".<ref name="Kaur2015"/> Knockout studies on mice and fruit flies support such a merged group.<ref name="pmid29171103">{{cite journal | vauthors = Marxreiter S, Thummel CS | title = Adult functions for the Drosophila DHR78 nuclear receptor | journal = Developmental Dynamics | volume = 247 | issue = 2 | pages = 315–322 | date = February 2018 | pmid = 29171103 | pmc = 5771960 | doi = 10.1002/dvdy.24608 }}</ref>

== Evolution ==
A topic of debate has been on the identity of the ancestral nuclear receptor as either a ligand-binding or an [[orphan receptor]]. This debate began more than twenty-five years ago when the first ligands were identified as mammalian steroid and thyroid hormones.<ref>{{cite journal | vauthors = Evans RM | title = The steroid and thyroid hormone receptor superfamily | journal = Science | volume = 240 | issue = 4854 | pages = 889–95 | date = May 1988 | pmid = 3283939 | pmc = 6159881 | doi = 10.1126/science.3283939 | bibcode = 1988Sci...240..889E }}</ref> Shortly thereafter, the identification of the ecdysone receptor in Drosophila introduced the idea that nuclear receptors were hormonal receptors that bind ligands with a nanomolar affinity. At the time, the three known nuclear receptor ligands were steroids, retinoids, and thyroid hormone, and of those three, both steroids and retinoids were products of terpenoid metabolism. Thus, it was postulated that ancestral receptor would have been liganded by a terpenoid molecule.<ref>{{cite journal | vauthors = Moore DD | title = Diversity and unity in the nuclear hormone receptors: a terpenoid receptor superfamily | journal = The New Biologist | volume = 2 | issue = 1 | pages = 100–5 | date = January 1990 | pmid = 1964083 }}</ref>

In 1992, a comparison of the DNA-binding domain of all known nuclear receptors led to the construction of a phylogenic tree of nuclear receptor that indicated that all nuclear receptors shared a common ancestor.<ref>{{cite journal | vauthors = Laudet V, Hänni C, Coll J, Catzeflis F, Stéhelin D | title = Evolution of the nuclear receptor gene superfamily | journal = The EMBO Journal | volume = 11 | issue = 3 | pages = 1003–13 | date = March 1992 | pmid = 1312460 | pmc = 556541 | doi = 10.1002/j.1460-2075.1992.tb05139.x }}</ref> As a result, there was an increased effort upon uncovering the state of the first nuclear receptor, and by 1997 an alternative hypothesis was suggested: the ancestral nuclear receptor was an orphan receptor and it acquired ligand-binding ability over time<ref name="Laudet_1997">{{cite journal | vauthors = Laudet V | title = Evolution of the nuclear receptor superfamily: early diversification from an ancestral orphan receptor | journal = Journal of Molecular Endocrinology | volume = 19 | issue = 3 | pages = 207–26 | date = December 1997 | pmid = 9460643 | doi = 10.1677/jme.0.0190207 | s2cid = 16419929 }}</ref> This hypothesis was proposed based on the following arguments:
# The nuclear receptor sequences that had been identified in the earliest metazoans (cnidarians and ''Schistosoma'') were all members of the COUP-TF, RXR, and FTZ-F1 groups of receptors. Both COUP-TF and FTZ-F1 are orphan receptors, and RXR is only found to bind a ligand in vertebrates.<ref>{{cite journal | vauthors = Escriva H, Safi R, Hänni C, Langlois MC, Saumitou-Laprade P, Stehelin D, Capron A, Pierce R, Laudet V | title = Ligand binding was acquired during evolution of nuclear receptors | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 94 | issue = 13 | pages = 6803–8 | date = June 1997 | pmid = 9192646 | doi = 10.1073/pnas.94.13.6803 | pmc=21239| bibcode = 1997PNAS...94.6803E | doi-access = free }}</ref>
# While orphan receptors had known arthropod homologs, no orthologs of liganded vertebrate receptors had been identified outside vertebrates, suggesting that orphan receptors are older than liganded-receptors.<ref name="Escriva_2000">{{cite journal | vauthors = Escriva H, Delaunay F, Laudet V | title = Ligand binding and nuclear receptor evolution | journal = BioEssays | volume = 22 | issue = 8 | pages = 717–27 | date = August 2000 | pmid = 10918302 | doi = 10.1002/1521-1878(200008)22:8<717::AID-BIES5>3.0.CO;2-I | s2cid = 45891497 }}</ref>
# Orphan receptors are found amongst all six subfamilies of nuclear receptors, while ligand-dependent receptors are found amongst three.<ref name="Laudet_1997"/> Thus, since the ligand-dependent receptors were believed to be predominantly member of recent subfamilies, it seemed logical that they gained the ability to bind ligands independently.
# The phylogenetic position of a given nuclear receptor within the tree correlates to its DNA-binding domain and dimerization abilities, but there is no identified relationship between a ligand-dependent nuclear receptor and the chemical nature of its ligand. In addition to this, the evolutionary relationships between ligand-dependent receptors did not make much sense as closely related receptors of subfamilies bound ligands originating from entirely different biosynthetic pathways (e.g. TRs and RARs). On the other hand, subfamilies that are not evolutionarily related bind similar ligands (RAR and RXR both bind all-trans and 9-cis retinoic acid respectively).<ref name="Escriva_2000" />
# In 1997, it was discovered that nuclear receptors did not exist in static off and on conformations, but that a ligand could alter the equilibrium between the two states. Furthermore, it was found that nuclear receptors could be regulated in a ligand-independent manner, through either phosphorylation or other post-translational modifications. Thus, this provided a mechanism for how an ancestral orphan receptor was regulated in a ligand-independent manner, and explained why the ligand binding domain was conserved.<ref name="Escriva_2000" />
Over the next 10 years, experiments were conducted to test this hypothesis and counterarguments soon emerged:
# Nuclear receptors were identified in the newly sequenced genome of the [[demosponge]] ''Amphimedon queenslandica'', a member Porifera, the most ancient metazoan phylum. The ''A. queenslandica'' genome contains two nuclear receptors known as AqNR1 and AqNR2 and both were characterized to bind and be regulated by ligands.<ref>{{cite journal | vauthors = Bridgham JT, Eick GN, Larroux C, Deshpande K, Harms MJ, Gauthier ME, Ortlund EA, Degnan BM, Thornton JW | title = Protein evolution by molecular tinkering: diversification of the nuclear receptor superfamily from a ligand-dependent ancestor | journal = PLOS Biology | volume = 8 | issue = 10 | pages = e1000497 | date = October 2010 | pmid = 20957188 | doi = 10.1371/journal.pbio.1000497 | pmc=2950128 | doi-access = free }}</ref>
# Homologs for ligand-dependent vertebrate receptors were found outside vertebrates in mollusks and Platyhelminthes. Furthermore, the nuclear receptors found in cnidarians were found to have structural ligands in mammals, which could mirror the ancestral situation.
# Two putative [[orphan receptor]]s, [[HNF4]] and [[Ultraspiracle protein|USP]] were found, via structural and mass spectrometry analysis, to bind fatty acids and phospholipids respectively.<ref name=Schewabe04>{{cite journal | vauthors = Schwabe JW, Teichmann SA | title = Nuclear receptors: the evolution of diversity | journal = Science's STKE | volume = 2004 | issue = 217 | pages = pe4 | date = January 2004 | pmid = 14747695 | doi = 10.1126/stke.2172004pe4 | s2cid = 20835274 }}</ref>
# Nuclear receptors and ligands are found to be a lot less specific than was previously thought. Retinoids can bind mammalian receptors other than RAR and RXR such as, PPAR, RORb, or COUP-TFII. Furthermore, RXR is sensitive to a wide range of molecules including retinoids, fatty acids, and phospholipids.<ref name="Markov_2011">{{cite journal | vauthors = Markov GV, Laudet V | title = Origin and evolution of the ligand-binding ability of nuclear receptors | journal = Molecular and Cellular Endocrinology | volume = 334 | issue = 1–2 | pages = 21–30 | date = March 2011 | pmid = 21055443 | doi = 10.1016/j.mce.2010.10.017 | series = Evolution of Nuclear Hormone Receptors | s2cid = 33537979 }}</ref>
# Study of steroid receptor evolution revealed that the ancestral steroid receptor could bind a ligand, estradiol. Conversely, the estrogen receptor found in mollusks is constitutively active and did not bind estrogen-related hormones. Thus, this provided an example of how an ancestral ligand-dependent receptor could lose its ability to bind ligands.<ref>{{cite journal | vauthors = Thornton JW, Need E, Crews D | title = Resurrecting the ancestral steroid receptor: ancient origin of estrogen signaling | journal = Science | volume = 301 | issue = 5640 | pages = 1714–7 | date = September 2003 | pmid = 14500980 | doi = 10.1126/science.1086185 | bibcode = 2003Sci...301.1714T | s2cid = 37628350 }}</ref>
A combination of this recent evidence, as well as an in-depth study of the physical structure of the nuclear receptor ligand binding domain has led to the emergence of a new hypothesis regarding the ancestral state of the nuclear receptor. This hypothesis suggests that the ancestral receptor may act as a lipid sensor with an ability to bind, albeit rather weakly, several different hydrophobic molecules such as, retinoids, steroids, hemes, and fatty acids. With its ability to interact with a variety of compounds, this receptor, through duplications, would either lose its ability for ligand-dependent activity, or specialize into a highly specific receptor for a particular molecule.<ref name="Markov_2011" />

== History ==
Below is a brief selection of key events in the history of nuclear receptor research.<ref name="Tata_2005"/>
* 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 V. Jensen|Elwood Jensen]] – isolated the [[estrogen receptor]]
* 1980s – cloning of the estrogen, glucocorticoid, and thyroid hormone receptors by [[Pierre Chambon]], [[Ronald M. Evans|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 Physiology or Medicine|Nobel Prize in Medicine]]

== See also ==
* [[NucleaRDB]]
* [[Thyroid hormone receptor]]
* [[Steroid hormone receptor]]
* [[receptor (biochemistry)|Receptors]]

== References ==
{{Reflist | colwidth = 32em | refs =

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<!-- <ref name = "Wu_2007">{{cite journal | vauthors = Wu W, Niles EG, Hirai H, LoVerde PT | title = Evolution of a novel subfamily of nuclear receptors with members that each contain two DNA binding domains | journal = BMC Evolutionary Biology | volume = 7 | pages = 27 | date = February 2007 | pmid = 17319953 | pmc = 1810520 | doi = 10.1186/1471-2148-7-27 }}</ref> -->

<ref name = "Zhang_2004">{{cite journal | vauthors = Zhang Z, Burch PE, Cooney AJ, Lanz RB, Pereira FA, Wu J, Gibbs RA, Weinstock G, Wheeler DA | title = Genomic analysis of the nuclear receptor family: new insights into structure, regulation, and evolution from the rat genome | journal = Genome Research | volume = 14 | issue = 4 | pages = 580–90 | date = April 2004 | pmid = 15059999 | pmc = 383302 | doi = 10.1101/gr.2160004 }}</ref>

<ref name = "Zivadinovic_2005">{{cite journal | vauthors = Zivadinovic D, Gametchu B, Watson CS | title = Membrane estrogen receptor-alpha levels in MCF-7 breast cancer cells predict cAMP and proliferation responses | journal = Breast Cancer Research | volume = 7 | issue = 1 | pages = R101–12 | year = 2005 | pmid = 15642158 | pmc = 1064104 | doi = 10.1186/bcr958 | doi-access = free }}</ref>

<ref name="Wu_2021"> {{cite journal | vauthors = Wu W, LoVerde PT | title = Identification and evolution of nuclear receptors in Platyhelminths | journal = PLOS ONE | volume = 16(8): e0250750 | year = 2021 | issue = 8 | pages = e0250750 | pmid = 34388160 | pmc = 8363021 | doi = 10.1371/journal.pone.0250750 | bibcode = 2021PLoSO..1650750W | doi-access = free }}</ref>

}}

== External links ==
* {{MeshName|Nuclear+Receptors}}
* {{cite web | url = http://www.iuphar-db.org/index_nh.jsp | title = The IUPHAR Compendium of the Pharmacology and Classification of the Nuclear Receptor Superfamily 2006E | access-date = 2008-02-21 | author = Vincent Laudet | date = 2006 | work = Nuclear Receptor Compendium | publisher = The International Union of Basic and Clinical Pharmacology | archive-date = 2015-04-02 | archive-url = https://web.archive.org/web/20150402123548/http://www.iuphar-db.org/index_nh.jsp | url-status = dead }}
* {{cite web | url = http://www.nuclear-receptor.com | title = ''Nuclear Receptor'' online journal | access-date = 2008-02-21 | work = Home page | publisher = published by BioMed Central (no longer accepting submissions since May 2007) }}
* {{cite web| url =http://nrr.georgetown.edu/NRR/nrrhome.htm| title =Nuclear Receptor Resource| access-date =2008-02-21| publisher =Georgetown University| archive-url =https://web.archive.org/web/20080511195543/http://nrr.georgetown.edu/NRR/nrrhome.htm| archive-date =2008-05-11| url-status =dead}}
* {{cite web | url = http://www.nursa.org/ | title = Nuclear Receptor Signaling Atlas (Receptors, Coactivators, Corepressors and Ligands) | access-date = 2008-02-21 | publisher = The NURSA Consortium | quote = an NIH-funded research consortium and database; includes open-access PubMed-indexed journal, ''Nuclear Receptor Signaling'' }}
* {{cite web | url = http://www.nrresource.org/ | title = Nuclear Receptor Resource | access-date = 2009-09-21 | publisher = Jack Vanden Heuvel }}

{{Transcription factors|g2|state=collapsed}}
{{Receptor/signaling modulators}}
{{Authority control}}

[[Category:Nuclear receptors|*]]