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'''Nuclear receptor'''s are a class of [[ligand (biochemistry)|ligand]] activated [[intracellular receptor|intracelluar]] [[transcription factor]]s which up or down regulate the [[Gene expression|expression]] of [[gene|genes]].
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[[Image:Nuclear receptor action.png|thumb|500px|'''Mechanism nuclear receptor action'''. This figure depicts the mechanism of a class I nuclear receptor (NR) which, in the absence of ligand, is located in the cytosol. Hormone binding triggers dissociation of heat shock proteins (HSP), dimerization, and translocation to the nucleus where it 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.]]
Nuclear receptors may be classified either according to mechanism (type I or II),<ref name="Novac">Novac N, Heinzel T. Nuclear receptors: overview and classification. Curr. Drug Targets Inflamm. Allergy. 2004; 3(4):335-46. PMID 15584884</ref> or [[Homology (biology)#Homology of sequences in genetics|sequence homology]] (NR subfamilies 0-6)<ref name="NRNC">Nuclear Receptors Nomenclature Committee. A unified nomenclature system for the nuclear receptor superfamily. Cell. 1999; 97(2):161-3. PMID 10219237</ref> (see respectively mechanism and homology classifications below).
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[[Image:NR_ligands.png|thumb|500px|Structures of selected endogenous nuclear receptor ligands and the name of the receptor that each binds to.]]
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In the field of [[molecular biology]], '''nuclear receptor'''s are a class of [[protein]]s found within the interior of cells that are responsible for sensing the presence of [[hormone|hormones]] and certain other molecules. In response, these nuclear receptors affected by the hormones work in concert with other proteins to regulate the [[Gene expression|expression]] of specific [[gene|genes]], thereby regulating the mechanisms of the body ([[Metabolism#Regulation_and_control|metabolism]], developmental characteristics, [[Homeostasis#Biological_homeostasis|homeostatic functions)]]
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Nuclear receptors have the ability to directly bind to [[DNA]] and regulate the expression of adjacent genes, hence these receptors are classified as [[transcription factor]]s.<ref name="Evans_1988">{{cite journal |author=Evans RM|title=The steroid and thyroid hormone receptor superfamily|journal= Science |volume= 240 |issue= 4854 |pages= 889-95 |year= 1988| doi = 10.1126/science.3283939 |pmid= 3283939}}</ref><ref name="pmid11459855">{{cite journal | author = Olefsky JM | title = Nuclear receptor minireview series | journal = J. Biol. Chem. | volume = 276 | issue = 40 | pages = 36863-4 | year = 2001 | pmid = 11459855 | doi = 10.1074/jbc.R100047200 | issn = }}</ref> The regulation of gene expression by nuclear receptors only happens when a [[ligand (biochemistry)|ligand]]—a molecule which affects the receptor's behavior—is present. More specifically, ligand binding to a nuclear receptor results in a [[chemical conformation|conformational]] change in the receptor which in turn activates the receptor resulting in [[Regulation_of_gene_expression#Up-regulation_and_down-regulation|up-regulation]] of gene expression.
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A unique property of nuclear receptors which differentiate them from other classes of [[receptor (biochemistry)|receptors]] is their ability to directly interact with and control the expression of [[genomic]] DNA. Consequently nuclear receptors play key roles in [[developmental biology|development]] and [[homeostasis#Biological_homeostasis|homeostasis]] of organisms. As discussed in more detail below, nuclear receptors may be classified either according to [[Nuclear_receptor#Mechanism_of_action|mechanism]]<ref name="Mangelsdorf_1995">{{cite journal |author=Mangelsdorf DJ, Thummel C, Beato M, Herrlich P, Schutz G, Umesono K, Blumberg B, Kastner P, Mark M, Chambon P, Evans RM|title=The nuclear receptor superfamily: the second decade|journal= Cell |volume= 83 |issue= 6 |pages= 835-9 |year= 1995| doi = 10.1016/0092-8674(95)90199-X |pmid= 8521507}}</ref><ref name="Novac_2004">{{cite journal |author=Novac N, Heinzel T|title=Nuclear receptors: overview and classification|journal= Curr Drug Targets Inflamm Allergy |volume= 3 |issue= 4 |pages= 335-46 |year= 2004| doi = |pmid= 15584884 | url = http://www.ingentaconnect.com/content/ben/cdtia/2004/00000003/00000004/art00002}}</ref> or [[Nuclear_receptor#Family_members|homology]].<ref name="NRNC_1999">{{cite journal |author=Nuclear Receptors Nomenclature Committee|title=A unified nomenclature system for the nuclear receptor superfamily|journal= Cell |volume= 97 |issue= 2 |pages= 161-3 |year= 1999| doi = 10.1016/S0092-8674(00)80726-6 |pmid= 10219237}}</ref><ref name="pmid9460643">{{cite journal | author = Laudet V | title = Evolution of the nuclear receptor superfamily: early diversification from an ancestral orphan receptor | journal = J. Mol. Endocrinol. | volume = 19 | issue = 3 | pages = 207-26 | year = 1997 | pmid = 9460643 | doi = 10.1677/jme.0.0190207 | issn = }}</ref>
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== Ligands ==
 
== Ligands ==
Ligands that bind to nuclear receptors include [[lipophilicity|lipophilic]] substances such as [[endogenous]] [[hormone]]s, vitamins A and D, drugs, and [[xenobiotic]] [[endocrine disruptor]]s. 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.
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Ligands that bind to and activate nuclear receptors include [[lipophilicity|lipophilic]] substances such as [[endogenous]] [[hormone]]s, vitamins A and D, and [[xenobiotic]] [[endocrine disruptor]]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 [[FDA]] approved drugs are nuclear receptors.<ref name="pmid17139284">{{cite journal | author = Overington JP, Al-Lazikani B, Hopkins AL | title = How many drug targets are there? | journal = Nature reviews. Drug discovery | volume = 5 | issue = 12 | pages = 993-6 | year = 2006 | pmid = 17139284 | doi = 10.1038/nrd2199 | issn = }}</ref>
 
A number of nuclear receptors, referred to as [[orphan receptor]]s, 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 [[constitutive androstane receptor|CAR]] and [[ Pregnane X receptor|PXR]] appear to function as xenobiotic sensors upregulating the expression of [[cytochrome P450]] enzymes that metabolize these xenobiotics.<ref name="Mohan">Mohan R, Heyman RA, Orphan nuclear receptor modulators. Curr Top Med Chem. 2003; 3(14):1637-47. PMID 14683519 </ref>
 
 
 
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.
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A number of nuclear receptors, referred to as [[orphan receptor]]s,<ref name="pmid17132856">{{cite journal | author = Benoit G, Cooney A, Giguere V, Ingraham H, Lazar M, Muscat G, Perlmann T, Renaud JP, Schwabe J, Sladek F, Tsai MJ, Laudet V | title = International Union of Pharmacology. LXVI. Orphan nuclear receptors | journal = Pharmacol. Rev. | volume = 58 | issue = 4 | pages = 798-836 | year = 2006 | pmid = 17132856 | doi = 10.1124/pr.58.4.10 | issn = }}</ref> 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">{{cite journal |author=Mohan R, Heyman RA|title=Orphan nuclear receptor modulators|journal= Curr Top Med Chem |volume= 3 |issue= 14 |pages= 1637-47 |year= 2003| doi = 10.2174/1568026033451709 |pmid= 14683519}}</ref>
   
== Structure<ref name="Klinge">Klinge CM, Estrogen receptor interaction with co-activators and co-repressors. Steroids. 2000; 65(5):227-51. PMID 10751636 </ref> ==
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== Structure ==
Nuclear receptors contain the following domains:
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[[Image:Nuclear Receptor Structure.png|thumb|500px|'''Structural Organization of Nuclear Receptors'''<br />'''Top''' – Schematic 1D 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 (E) have not been determined therefore are represented by red, purple, and orange dashed lines respectively.]]
*A-B) N-terminal regulatory domain
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Nuclear receptors are modular in structure and contain the following [[structural domain|domains]]:<ref name="pmid10406480">{{cite journal | author = Kumar R, Thompson EB | title = The structure of the nuclear hormone receptors | journal = Steroids | volume = 64 | issue = 5 | pages = 310–9 | year = 1999 | pmid = 10406480 | doi = 10.1016/S0039-128X(99)00014-8 | issn = }}</ref><ref name="Klinge_2000">{{cite journal |author=Klinge CM|title=Estrogen receptor interaction with co-activators and co-repressors|journal= Steroids |volume= 65 |issue= 5 |pages= 227-51 |year= 2000 | doi = 10.1016/S0039-128X(99)00107-5 |pmid= 10751636}}</ref><br /><br />
*C) [[DNA-binding domain]] (DBD). (An unusual group of NRs contain two DBDs in tandem)<ref name="Niles">Wu W, Niles EG, El-Sayed N, Berriman M, LoVerde PT. 2006 Schistosoma mansoni (Platyhelminthes, Trematoda) nuclear receptors: sixteen new members and a novel subfamily. Gene. 366(2):303-15. PMID 16406405</ref><ref name="Wu"> 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, 7:27.PMID 17319953</ref>
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*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="pmid12893880">{{cite journal | author = Wärnmark A, Treuter E, Wright AP, Gustafsson J-Å | title = Activation functions 1 and 2 of nuclear receptors: molecular strategies for transcriptional activation | journal = Mol. Endocrinol. | volume = 17 | issue = 10 | pages = 1901-9 | year = 2003 | pmid = 12893880 | doi = 10.1210/me.2002-0384 | issn = }}</ref> The transcriptional activation of AF-1 is normally very weak, but it does synergize with AF-2 (see below) to produce a more robust upregulation of gene expression. The A-B domain is highly variable in sequence between various nuclear receptors.<br /><br />
*D) Hinge region
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*C) '''[[DNA-binding domain]] (DBD)''' ({{InterPro|IPR001628}}): Highly conserved domain containing two [[zinc finger]]s ({{SCOP|57715}}) which binds to specific sequences of DNA called [[hormone response element]]s (HRE).<br /><br />
*E) Ligand binding domain (LBD)
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*D) '''Hinge region''': Thought to be a flexible domain which connects the DBD with the LBD. Influences intracellular trafficking and subcellular distribution.<br /><br />
*F) C-terminal domain
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*E) '''Ligand binding domain (LBD)''' ({{InterPro|IPR000536}}): 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]] ({{SCOP|48507}}) 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. Contains the activation function 2 (AF-2) whose action is dependent on the presence of bound ligand.<ref name="pmid12893880" /><br /><br />
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*F) '''[[C-terminus|C-terminal]] domain''': Variable in sequence between various nuclear receptors.
   
== Mechanism classification<ref name="Novac"/> ==
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== Mechanism of action ==
Ligand binding to type I nuclear receptors (includes members of the NR subfamily 3) results in the [[Dissociation (chemistry)|dissociation]] of [[heat shock protein]]s, 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 element]]s (HRE's). The nuclear receptor/DNA [[complex (chemistry)|complex]] then recruits other proteins which [[Transcription (genetics)|transcribe]] DNA downstream from the HRE into [[messenger RNA]] and eventually [[protein]] which causes a change in cell function.
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[[Image:Type ii nuclear receptor action.png|thumb|500px|'''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 thyroid hormone receptor (TR) heterodimerized to RXR. In the absence of ligand, TR is bound to corepressor protein. Ligand binding to TR causes a dissociation of corepressor and recruitment of coactivator protein which in turn recruit additional proteins such as RNA polymerase that are responsible for translation of downstream DNA into RNA and eventually protein which results in a change in cell function.]]
   
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Nuclear receptors (NRs) may be classified into two broad classes according to their mechanism of action and subcellular distribution in the absence of ligand.
   
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 [[Retinoid X receptor|RXR]]) to DNA.
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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.
   
== Homology classification<ref name="NRNC"/> ==
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Accordingly, nuclear receptors may be subdivided into the following two mechanistic classes:<ref name="Mangelsdorf_1995"/><ref name="Novac_2004"/>
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===Type I===
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Ligand binding to type I nuclear receptors in the cytosol (includes members of the NR subfamily 3) results in the [[Dissociation (chemistry)|dissociation]] of [[heat shock protein]]s, 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 element]]s (HRE's). 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).
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The nuclear receptor/DNA [[complex (chemistry)|complex]] then recruits other proteins which [[Transcription (genetics)|transcribe]] DNA downstream from the HRE into [[messenger RNA]] and eventually [[protein]] which causes a change in cell function.
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===Type II===
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Type II receptors (principally 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 [[Retinoid X receptor|RXR]]) to DNA. 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 which translate DNA into messenger RNA.
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===Type III===
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Type III nuclear receptors (principally NR subfamily 2) are similar to type I receptors in that both classes bind to DNA has homodimers. However type III in contrast type I nuclear receptors bind to direct repeat instead of [[inverted repeat]] HREs.
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===Type IV===
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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.
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== Coregulatory proteins ==
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Nuclear receptors bound to hormone response elements recruit a significant number of other proteins (referred to as [[transcription coregulator]]s) which facilitate or inhibit the transcription of the associated target gene into mRNA.<ref name="Glass_2000">{{cite journal |author=Glass CK, Rosenfeld MG|title=The coregulator exchange in transcriptional functions of nuclear receptors|journal= Genes Dev |volume= 14 |issue= 2 |pages= 121-41 |year= 2000| doi = 10.1101/gad.14.2.121 |pmid= 10652267}}</ref><ref name="pmid11427696">{{cite journal | author = Aranda A, Pascual A | title = Nuclear hormone receptors and gene expression | journal = Physiol. Rev. | volume = 81 | issue = 3 | pages = 1269-304 | year = 2001 | pmid = 11427696 | doi = | issn =| url = http://physrev.physiology.org/cgi/content/abstract/81/3/1269 }}</ref> 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.
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=== Coactivators ===
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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.
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=== Corepressors ===
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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.
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== Agonism vs Antagonism ==
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[[Image:NR_mechanism.png|thumb|500px|'''Stuctural basis for the mechanism of nuclear receptor agonist and antagonist action.'''<ref name="Brzozowski_1997">{{cite journal |author=Brzozowski AM, Pike AC, Dauter Z, Hubbard RE, Bonn T, Engström O, Öhman L, Greene GL, Gustafsson J-Å, Carlquist M|title=Molecular basis of agonism and antagonism in the oestrogen receptor|journal= Nature |volume= 389 |issue= 6652 |pages= 753-8 |year= 1997| doi = 10.1038/39645 |pmid= 9338790}}</ref> 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">{{cite journal |author=Shiau AK, Barstad D, Loria PM, Cheng L, Kushner PJ, Agard DA, Greene GL |title=The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen |journal= Cell |volume= 95 |issue= 7 |pages= 927-37 |year= 1998 | doi = 10.1016/S0092-8674(00)81717-1 |pmid= 9875847}}</ref> 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.]]
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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="pmid15520817">{{cite journal | author = Gronemeyer H, Gustafsson JA, Laudet V | title = Principles for modulation of the nuclear receptor superfamily | journal = Nature reviews. Drug discovery | volume = 3 | issue = 11 | pages = 950-64 | year = 2004 | pmid = 15520817 | doi = 10.1038/nrd1551 | issn = }}</ref>
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=== Agonists ===
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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]] antiiflammatory 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).
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=== Antagonists ===
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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 block 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).
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=== Inverse agonists ===
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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.
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=== Selective receptor modulators ===
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A number of drugs that work through nuclear receptors display an agonist response in some tissue while 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 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">{{cite journal |author=Smith CL, O'Malley BW|title=Coregulator function: a key to understanding tissue specificity of selective receptor modulators|journal= Endocr Rev |volume= 25 |issue= 1 |pages= 45-71 |year= 2004 | doi = 10.1210/er.2003-0023 |pmid= 14769827}}</ref>
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== Alternative mechanisms ==
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=== Transrepression ===
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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 '''transrepresson'''.<ref name="Pascual_2006">{{cite journal |author=Pascual G, Glass CK|title=Nuclear receptors versus inflammation: mechanisms of transrepression|journal= Trends Endocrinol Metab |volume= 17 |issue= 8 |pages= 321-7 |year= 2006 | doi =10.1016/j.tem.2006.08.005 |pmid= 16942889}}</ref>
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=== Non-genomic ===
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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 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">{{cite journal |author=Björnström L, Sjöberg M|title=Estrogen receptor-dependent activation of AP-1 via non-genomic signalling|journal= Nucl Recept |volume= 2 |issue= 1 |pages= 3 |year= 2004 | doi =10.1186/1478-1336-2-3 |pmid= 15196329}}</ref><ref name="pmid15642158">{{cite journal | author = 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 Res. | volume = 7 | issue = 1 | pages = R101-12 | year = 2005 | pmid = 15642158 | doi = 10.1186/bcr958}}</ref>
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== Family members ==
 
<!-- This list is mirrored on [[receptor (biochemistry)]] and [[intracellular receptor]]; please update all simultaneously -->
 
<!-- This list is mirrored on [[receptor (biochemistry)]] and [[intracellular receptor]]; please update all simultaneously -->
   
The following is a list of the 48 known human nuclear receptors<ref name="Zhang">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. PMID 15059999</ref> sorted according to sequence homology.
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The following is a list of the 48 known human nuclear receptors<ref name="Zhang_2004">{{cite journal |author=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 Res |volume= 14 |issue= 4 |pages= 580-90 |year= 2004 | doi = 10.1101/gr.2160004 |pmid= 15059999}}</ref> categorized according to [[Homology (biology)#Homology of sequences in genetics|sequence homology]].<ref name="NRNC_1999"/><ref name="pmid9460643"/> The list is organized as follows:
   
*Subfamily:Group:Member: Name (Abbreviation; NRNC Symbol - Nuclear Receptor Nomenclature Committee<ref name="NRNC"/>) (endogenous ligand)
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*Subfamily 1: Thyroid Hormone Receptor-like
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'''Subfamily''': name
**Group A: [[Thyroid hormone receptor]] ([[Thyroid hormone]])
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:Group: name (endogenous ligand if common to entire group)
***1: Thyroid hormone receptor-α (TRα; NR1A1)
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::Member: name (abbreviation; NRNC Symbol<ref name="NRNC_1999"/>, gene) (endogenous ligand)
***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|HNF4]])
+
[[Image:Nr_alignment_tree.jpg|thumb|500px|'''Phylogenetic tree of human nuclear receptors''']]
***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]])
+
===Subfamily 1: Thyroid Hormone Receptor-like===
**Group A: [[Estrogen receptor]] ([[Sex hormone receptor]]s; [[sex hormone]]s: [[Estrogen]])
+
*Group A: [[Thyroid hormone receptor]] ([[Thyroid hormone]])
***1: Estrogen receptor-α (ERα; NR3A1)
+
**1: Thyroid hormone receptor-α ([[thyroid hormone receptor alpha|TRα]]; NR1A1, {{Gene|THRA}})
***2: Estrogen receptor-β (ERβ; NR3A2)
+
**2: Thyroid hormone receptor-β ([[thyroid hormone receptor beta|TRβ]]; NR1A2, {{Gene|THRB}})
**Group B: [[Estrogen related receptor]]
+
*Group B: [[Retinoic acid receptor]] ([[Vitamin A]] and related compounds)
***1: Estrogen related receptor-α (ERRα; NR3B1)
+
**1: Retinoic acid receptor-α ([[retinoic acid receptor alpha|RARα]]; NR1B1, {{Gene|RARA}})
***2: Estrogen related receptor-β (ERRβ; NR3B2)
+
**2: Retinoic acid receptor-β ([[retinoic acid receptor beta|RARβ]]; NR1B2, {{Gene|RARB}})
***3: Estrogen related receptor-γ (ERRγ; NR3B3)
+
**3: Retinoic acid receptor-γ ([[retinoic acid receptor gamma|RARγ]]; NR1B3, {{Gene|RARG}})
**Group C: 3-Ketosteroid receptors
+
*Group C: [[Peroxisome proliferator-activated receptor]]
***1: [[Glucocorticoid receptor]] (GR; NR3C1) ([[Cortisol]])
+
**1: Peroxisome proliferator-activated receptor ([[peroxisome proliferator-activated receptor alpha|PPARα]]; NR1C1, {{Gene|PPARA}})
***2: [[Mineralocorticoid receptor]] (MR; NR3C2) ([[Aldosterone]])
+
**2: Peroxisome proliferator-activated receptor-β/δ ([[peroxisome proliferator-activated receptor delta|PPARβ/δ]]; NR1C2, {{Gene|PPARD}})
***3: [[Progesterone receptor]] (PR; NR3C3) ([[Sex hormone receptor]]; [[Sex hormone]]s: [[Progesterone]])
+
**3: Peroxisome proliferator-activated receptor ([[peroxisome proliferator-activated receptor gamma|PPARγ]]; NR1C3, {{Gene|PPARG}})
***4: [[Androgen receptor]] (AR; NR3C4) ([[Sex hormone receptor]]s; [[Sex hormone]]s: [[Testosterone]])
+
*Group D: [[Rev-ErbA]]
  +
**1: Rev-ErbAα ([[Rev-ErbA alpha|Rev-ErbAα]]; {{Gene|NR1D1}})
  +
**2: Rev-ErbAβ ([[Rev-ErbA beta|Rev-ErbAβ]]; {{Gene|NR1D2}})
  +
*Group F: [[RAR-related orphan receptor]]
  +
**1: RAR-related orphan receptor-α ([[RAR-related orphan receptor alpha|RORα]]; NR1F1, {{Gene|RORA}})
  +
**2: RAR-related orphan receptor-β ([[RAR-related orphan receptor beta|RORβ]]; NR1F2, {{Gene|RORB}})
  +
**3: RAR-related orphan receptor-γ ([[RAR-related orphan receptor gamma|RORγ]]; NR1F3, {{Gene|RORC}})
  +
*Group H: [[Liver X receptor]]-like
  +
**3: Liver X receptor-α ([[liver X receptor alpha|LXRα]]; {{Gene|NR1H3}})
  +
**2: Liver X receptor-β ([[liver X receptor beta|LXRβ]]; {{Gene|NR1H2}})
  +
**4: Farnesoid X receptor ([[Farnesoid X receptor|FXR]]; {{Gene|NR1H4}})
  +
*Group I: Vitamin D receptor-like
  +
**1: Vitamin D receptor ([[Vitamin D receptor|VDR]]; NR1I1, {{Gene|VDR}}) ([[vitamin D]])
  +
**2: Pregnane X receptor ([[Pregnane X receptor|PXR]]; {{Gene|NR1I2}})
  +
**3: Constitutive androstane receptor ([[Constitutive androstane receptor|CAR]]; {{Gene|NR1I3}})
   
*Subfamily 4: Nerve Growth Factor IB-like
+
===Subfamily 2: Retinoid X Receptor-like===
**Group A: NGFIB/NURR1/NOR1
+
*Group A: [[Hnf4|Hepatocyte nuclear factor-4]] (HNF4)
***1: Nerve Growth factor IB (NGFIB; NR4A1)
+
**1: Hepatocyte nuclear factor-4-α ([[hepatocyte nuclear factor 4 alpha|HNF4α]]; NR2A1, {{Gene|HNF4A}})
***2: Nuclear receptor related 1 (NURR1; NR4A2)
+
**2: Hepatocyte nuclear factor-4-γ ([[hepatocyte nuclear factor 4 gamma|HNF4γ]]; NR2A2, {{Gene|HNF4G}})
***3: Neuron-derived orphan receptor 1 (NOR1; NR4A3)
+
*Group B: [[Retinoid X receptor]] (RXRα)
  +
**1: Retinoid X receptor-α ([[retinoid X receptor alpha|RXRα]]; NR2B1, {{Gene|RXRA}})
  +
**2: Retinoid X receptor-β ([[retinoid X receptor beta|RXRβ]]; NR2B2, {{Gene|RXRB}})
  +
**3: Retinoid X receptor-γ ([[retinoid X receptor gamma|RXRγ]]; NR2B3, {{Gene|RXRG}})
  +
*Group C: [[Testicular receptor]]
  +
**1: Testicular receptor 2 ([[testicular receptor 2|TR2]]; {{Gene|NR2C1}})
  +
**2: Testicular receptor 4 ([[testicular receptor 4|TR4]]; {{Gene|NR2C2}})
  +
*Group E: TLX/PNR
  +
**1: Human homologue of the Drosophila tailless gene ([[TLX]]; {{Gene|NR2E1}})
  +
**3: Photoreceptor cell-specific nuclear receptor ([[Photoreceptor cell-specific nuclear receptor|PNR]]; {{Gene|NR2E3}})
  +
*Group F: [[Chicken ovalbumin upstream promoter-transcription factor|COUP]]/EAR
  +
**1: Chicken ovalbumin upstream promoter-transcription factor I ([[COUP-TFI]]; {{Gene|NR2F1}})
  +
**2: Chicken ovalbumin upstream promoter-transcription factor II ([[COUP-TFII]]; {{Gene|NR2F2}})
  +
**6: V-erbA-related gene|V-erbA-related ([[V-erbA-related gene|EAR-2]]; {{Gene|NR2F6}})
   
*Subfamily 5: Steroidogenic Factor-like
+
===Subfamily 3: Estrogen Receptor-like ===
**Group A: SF1/LRH1
+
''See also [[steroid hormone receptors|steroid]] and [[sex hormone receptor]]s''
***1: Steroidogenic factor 1 (SF1; NR5A1)
+
*Group A: [[Estrogen receptor]] ([[Sex hormone]]s: [[Estrogen]])
***2: Liver receptor homolog 1 (LRH1; NR5A2)
+
**1: Estrogen receptor ([[estrogen receptor alpha|ERα]]; NR3A1, {{Gene|ESR1}})
  +
**2: Estrogen receptor-β ([[estrogen receptor beta|ERβ]]; NR3A2, {{Gene|ESR2}})
  +
*Group B: [[Estrogen related receptor]]
  +
**1: Estrogen-related receptor-α ([[estrogen-related receptor alpha|ERRα]]; NR3B1, {{Gene|ESRRA}})
  +
**2: Estrogen-related receptor-β ([[estrogen-related receptor beta|ERRβ]]; NR3B2, {{Gene|ESRRB}})
  +
**3: Estrogen-related receptor-γ ([[estrogen-related receptor gamma|ERRγ]]; NR3B3, {{Gene|ESRRG}})
  +
*Group C: 3-Ketosteroid receptors
  +
**1: Glucocorticoid receptor ([[glucocorticoid receptor|GR]]; {{Gene|NR3C1}}) ([[Cortisol]])
  +
**2: Mineralocorticoid receptor ([[mineralocorticoid receptor|MR]]; {{Gene|NR3C2}}) ([[Aldosterone]])
  +
**3: Progesterone receptor ([[progesterone receptor|PR]]; NR3C3, {{Gene|PGR}}) ([[Sex hormone]]s: [[Progesterone]])
  +
**4: Androgen receptor ([[androgen receptor|AR]]; NR3C4, {{Gene|AR}}) ([[Sex hormone]]s: [[Testosterone]])
   
*Subfamily 6: Germ Cell Nuclear Factor-like
+
===Subfamily 4: Nerve Growth Factor IB-like===
**Group A: GCN1
+
*Group A: NGFIB/NURR1/NOR1
***1: Germ cell nuclear factor (GCN1; NR6A1)
+
**1: Nerve Growth factor IB ([[Nerve Growth factor IB|NGFIB]]; {{Gene|NR4A1}})
  +
**2: Nuclear receptor related 1 ([[Nuclear receptor related 1 protein|NURR1]]; {{Gene|NR4A2}})
  +
**3: Neuron-derived orphan receptor 1 ([[Neuron-derived orphan receptor 1|NOR1]]; {{Gene|NR4A3}})
   
*Subfamily 0: Miscellaneous
+
===Subfamily 5: Steroidogenic Factor-like===
**Group B: DAX/SHP
+
*Group A: SF1/LRH1
***1: Dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1 (DAX-1; [[NR0B1]])
+
**1: Steroidogenic factor 1 ([[Steroidogenic factor 1|SF1]]; {{Gene|NR5A1}})
***2: Short heterodimer partner (SHP; NR0B2)
+
**2: Liver receptor homolog-1 ([[Liver receptor homolog-1|LRH-1]]; {{Gene|NR5A2}})
   
  +
===Subfamily 6: Germ Cell Nuclear Factor-like===
  +
*Group A: GCNF
  +
**1: Germ cell nuclear factor ([[Germ cell nuclear factor|GCNF]]; {{Gene|NR6A1}})
   
*Subfamily 7: Nuclear receptors with two DNA binding domains (2DBD-NR) (A novel subfamily)<ref name="Niles">Wu W, Niles EG, El-Sayed N, Berriman M, LoVerde PT. 2006 Schistosoma mansoni (Platyhelminthes, Trematoda) nuclear receptors: sixteen new members and a novel subfamily. Gene. 366(2):303-15. PMID 16406405</ref><ref name="Wu"> 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, 7:27.PMID 17319953</ref>
+
===Subfamily 0: Miscellaneous===
  +
*Group B: DAX/SHP
  +
**1: Dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1 ([[DAX1]], {{Gene|NR0B1}})
  +
**2: Small heterodimer partner ([[Small heterodimer partner|SHP]]; {{Gene|NR0B2}})
  +
*Group C: Nuclear receptors with two DNA binding domains (2DBD-NR) (A novel subfamily)<ref name="Wu_2006">{{cite journal |author=Wu W, Niles EG, El-Sayed N, Berriman M, LoVerde PT|title=Schistosoma mansoni (Platyhelminthes, Trematoda) nuclear receptors: sixteen new members and a novel subfamily|journal= Gene |volume= 366 |issue= 2 |pages= 303-15 |year= 2006 | doi = 10.1016/j.gene.2005.09.013 |pmid= 16406405}}</ref><ref name="Wu_2007">{{cite journal |author=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= Feb 23 |pages= 27 |year= 2004 | doi = 10.1186/1471-2148-7-27 |pmid= 17319953}}</ref>
  +
  +
== History of nuclear receptors ==
  +
  +
Below is a brief selection of key events in the history of nuclear receptor research.<ref name="pmid15940278">{{cite journal | author = Tata JR | title = One hundred years of hormones | journal = EMBO Rep. | volume = 6 | issue = 6 | pages = 490-6 | year = 2005 | pmid = 15940278 | doi = 10.1038/sj.embor.7400444 | issn = }}</ref>
  +
  +
* 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]]
  +
* 1961 - [[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 ==
 
== See also ==
Line 79: Line 83:
 
* [[Transcription factor]]
 
* [[Transcription factor]]
   
+
==References==
  +
{{Reflist|2}}
   
 
== External links ==
 
== External links ==
+
*[http://www.iuphar-db.org/index_nh.jsp The IUPHAR Compendium of the Pharmacology and Classification of the Nuclear Receptor Superfamily 2006]
* [http://www.nuclear-receptor.com/ ''Nuclear Receptor'' journal homepage]
+
* [http://www.nuclear-receptor.com/ ''Nuclear Receptor'' online journal] published by BioMed Central
 
* [http://nrr.georgetown.edu/NRR/nrrhome.htm Nuclear receptor resource] at Georgetown University
 
* [http://nrr.georgetown.edu/NRR/nrrhome.htm Nuclear receptor resource] at Georgetown University
 
* [http://www.nursa.org/ Nuclear Receptor Signalling Atlas] (NURSA, NIH-funded research consortium and database; includes open-access PubMed-indexed journal, <i>Nuclear Receptor Signaling</i>)
 
* [http://www.nursa.org/ Nuclear Receptor Signalling Atlas] (NURSA, NIH-funded research consortium and database; includes open-access PubMed-indexed journal, <i>Nuclear Receptor Signaling</i>)
Line 90: Line 94:
 
{{Transcription factors}}
 
{{Transcription factors}}
 
[[Category:Intracellular receptors]]
 
[[Category:Intracellular receptors]]
  +
[[Category:Transcription factors]]
   
:sv:Nukleära receptorer
+
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  +
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  +
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{{enWP|Nuclear receptor}}
 
{{enWP|Nuclear receptor}}

Latest revision as of 01:28, January 25, 2008

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File:Nuclear receptor action.png
File:NR ligands.png

In the field of molecular biology, nuclear receptors are a class of proteins found within the interior of cells that are responsible for sensing the presence of hormones and certain other molecules. In response, these nuclear receptors affected by the hormones work in concert with other proteins to regulate the expression of specific genes, thereby regulating the mechanisms of the body (metabolism, developmental characteristics, homeostatic functions)

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.[1][2] The regulation of gene expression by nuclear receptors only happens when a ligand—a molecule which 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 of gene expression.

A unique property of nuclear receptors which differentiate them from other classes of receptors is their ability to directly interact with and control the expression of genomic DNA. Consequently nuclear receptors play key roles in development and homeostasis of organisms. As discussed in more detail below, nuclear receptors may be classified either according to mechanism[3][4] or homology.[5][6]

Ligands Edit

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 FDA approved drugs are nuclear receptors.[7]

A number of nuclear receptors, referred to as orphan receptors,[8] 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.[9]

Structure Edit

File:Nuclear Receptor Structure.png

Nuclear receptors are modular in structure and contain the following domains:[10][11]

  • A-B) N-terminal regulatory domain: Contains the activation function 1 (AF-1) whose action is independent of the presence of ligand.[12] The transcriptional activation of AF-1 is normally very weak, but it does synergize with AF-2 (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) (Template:InterPro): Highly conserved domain containing two zinc fingers (Template:SCOP) which binds to specific sequences of DNA called hormone response elements (HRE).

  • D) Hinge region: Thought to be a flexible domain which connects the DBD with the LBD. Influences intracellular trafficking and subcellular distribution.

  • E) Ligand binding domain (LBD) (Template:InterPro): 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 (Template:SCOP) 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. Contains the activation function 2 (AF-2) whose action is dependent on the presence of bound ligand.[12]

  • F) C-terminal domain: Variable in sequence between various nuclear receptors.

Mechanism of action Edit

File:Type ii nuclear receptor action.png

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.

Accordingly, nuclear receptors may be subdivided into the following two mechanistic classes:[3][4]

Type IEdit

Ligand binding to type I nuclear receptors in the cytosol (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). 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).

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 IIEdit

Type II receptors (principally 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. 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 which translate DNA into messenger RNA.

Type IIIEdit

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

Type IVEdit

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 Edit

Nuclear receptors bound to hormone response elements recruit a significant number of other proteins (referred to as transcription coregulators) which facilitate or inhibit the transcription of the associated target gene into mRNA.[13][14] 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 Edit

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 Edit

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 Edit

File:NR mechanism.png

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.[17]

Agonists Edit

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 antiiflammatory 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 Edit

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 block 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 Edit

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.

Selective receptor modulators Edit

A number of drugs that work through nuclear receptors display an agonist response in some tissue while 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 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.[18]

Alternative mechanisms Edit

Transrepression Edit

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 transrepresson.[19]

Non-genomic Edit

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 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.[20][21]

Family members Edit

The following is a list of the 48 known human nuclear receptors[22] categorized according to sequence homology.[5][6] The list is organized as follows:


Subfamily: name

Group: name (endogenous ligand if common to entire group)
Member: name (abbreviation; NRNC Symbol[5], gene) (endogenous ligand)

File:Nr alignment tree.jpg

Subfamily 1: Thyroid Hormone Receptor-likeEdit

Subfamily 2: Retinoid X Receptor-likeEdit

Subfamily 3: Estrogen Receptor-like Edit

See also steroid and sex hormone receptors

Subfamily 4: Nerve Growth Factor IB-likeEdit

  • Group A: NGFIB/NURR1/NOR1

Subfamily 5: Steroidogenic Factor-likeEdit

  • Group A: SF1/LRH1

Subfamily 6: Germ Cell Nuclear Factor-likeEdit

  • Group A: GCNF

Subfamily 0: MiscellaneousEdit

  • Group B: DAX/SHP
    • 1: Dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1 (DAX1, NR0B1)
    • 2: Small heterodimer partner (SHP; NR0B2)
  • Group C: Nuclear receptors with two DNA binding domains (2DBD-NR) (A novel subfamily)[23][24]

History of nuclear receptors Edit

Below is a brief selection of key events in the history of nuclear receptor research.[25]

See also Edit

ReferencesEdit

  1. Evans RM (1988). The steroid and thyroid hormone receptor superfamily. Science 240 (4854): 889-95.
  2. Olefsky JM (2001). Nuclear receptor minireview series. J. Biol. Chem. 276 (40): 36863-4.
  3. 3.0 3.1 Mangelsdorf DJ, Thummel C, Beato M, Herrlich P, Schutz G, Umesono K, Blumberg B, Kastner P, Mark M, Chambon P, Evans RM (1995). The nuclear receptor superfamily: the second decade. Cell 83 (6): 835-9.
  4. 4.0 4.1 Novac N, Heinzel T (2004). Nuclear receptors: overview and classification. Curr Drug Targets Inflamm Allergy 3 (4): 335-46.
  5. 5.0 5.1 5.2 Nuclear Receptors Nomenclature Committee (1999). A unified nomenclature system for the nuclear receptor superfamily. Cell 97 (2): 161-3.
  6. 6.0 6.1 Laudet V (1997). Evolution of the nuclear receptor superfamily: early diversification from an ancestral orphan receptor. J. Mol. Endocrinol. 19 (3): 207-26.
  7. Overington JP, Al-Lazikani B, Hopkins AL (2006). How many drug targets are there?. Nature reviews. Drug discovery 5 (12): 993-6.
  8. Benoit G, Cooney A, Giguere V, Ingraham H, Lazar M, Muscat G, Perlmann T, Renaud JP, Schwabe J, Sladek F, Tsai MJ, Laudet V (2006). International Union of Pharmacology. LXVI. Orphan nuclear receptors. Pharmacol. Rev. 58 (4): 798-836.
  9. Mohan R, Heyman RA (2003). Orphan nuclear receptor modulators. Curr Top Med Chem 3 (14): 1637-47.
  10. Kumar R, Thompson EB (1999). The structure of the nuclear hormone receptors. Steroids 64 (5): 310–9.
  11. Klinge CM (2000). Estrogen receptor interaction with co-activators and co-repressors. Steroids 65 (5): 227-51.
  12. 12.0 12.1 Wärnmark A, Treuter E, Wright AP, Gustafsson J-Å (2003). Activation functions 1 and 2 of nuclear receptors: molecular strategies for transcriptional activation. Mol. Endocrinol. 17 (10): 1901-9.
  13. Glass CK, Rosenfeld MG (2000). The coregulator exchange in transcriptional functions of nuclear receptors. Genes Dev 14 (2): 121-41.
  14. Aranda A, Pascual A (2001). Nuclear hormone receptors and gene expression. Physiol. Rev. 81 (3): 1269-304.
  15. Brzozowski AM, Pike AC, Dauter Z, Hubbard RE, Bonn T, Engström O, Öhman L, Greene GL, Gustafsson J-Å, Carlquist M (1997). Molecular basis of agonism and antagonism in the oestrogen receptor. Nature 389 (6652): 753-8.
  16. Shiau AK, Barstad D, Loria PM, Cheng L, Kushner PJ, Agard DA, Greene GL (1998). The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen. Cell 95 (7): 927-37.
  17. Gronemeyer H, Gustafsson JA, Laudet V (2004). Principles for modulation of the nuclear receptor superfamily. Nature reviews. Drug discovery 3 (11): 950-64.
  18. Smith CL, O'Malley BW (2004). Coregulator function: a key to understanding tissue specificity of selective receptor modulators. Endocr Rev 25 (1): 45-71.
  19. Pascual G, Glass CK (2006). Nuclear receptors versus inflammation: mechanisms of transrepression. Trends Endocrinol Metab 17 (8): 321-7.
  20. Björnström L, Sjöberg M (2004). Estrogen receptor-dependent activation of AP-1 via non-genomic signalling. Nucl Recept 2 (1): 3.
  21. Zivadinovic D, Gametchu B, Watson CS (2005). Membrane estrogen receptor-alpha levels in MCF-7 breast cancer cells predict cAMP and proliferation responses. Breast Cancer Res. 7 (1): R101-12.
  22. Zhang Z, Burch PE, Cooney AJ, Lanz RB, Pereira FA, Wu J, Gibbs RA, Weinstock G, Wheeler DA (2004). Genomic analysis of the nuclear receptor family: new insights into structure, regulation, and evolution from the rat genome. Genome Res 14 (4): 580-90.
  23. Wu W, Niles EG, El-Sayed N, Berriman M, LoVerde PT (2006). Schistosoma mansoni (Platyhelminthes, Trematoda) nuclear receptors: sixteen new members and a novel subfamily. Gene 366 (2): 303-15.
  24. Wu W, Niles EG, Hirai H, LoVerde PT (2004). Evolution of a novel subfamily of nuclear receptors with members that each contain two DNA binding domains. BMC Evol Biol 7 (Feb 23): 27.
  25. Tata JR (2005). One hundred years of hormones. EMBO Rep. 6 (6): 490-6.

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