Summary: Ligand-binding domain of nuclear hormone receptor
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Nuclear receptor Edit Wikipedia article
In the field of molecular biology, nuclear receptors are a class of proteins found within cells that are responsible for sensing steroid and thyroid hormones and certain other molecules. In response, these receptors work with other proteins to regulate the expression of specific genes, thereby controlling the development, homeostasis, and metabolism of the organism.
Nuclear receptors have the ability to directly bind to DNA and regulate the expression of adjacent genes, hence these receptors are classified as transcription factors. The regulation of gene expression by nuclear receptors generally only happens when a ligand â€” a molecule that affects the receptor's behavior â€” 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- or down-regulation of gene expression.
A unique property of nuclear receptors that differentiates them from other classes of receptors is their ability to directly interact with and control the expression of genomic DNA. As a consequence, nuclear receptors play key roles in both embryonic development and adult homeostasis. As discussed below, nuclear receptors may be classified according to either mechanism or homology.
- 1 Species distribution
- 2 Ligands
- 3 Structure
- 4 Mechanism of action
- 5 Coregulatory proteins
- 6 Agonism vs antagonism
- 7 Alternative mechanisms
- 8 Family members
- 9 Evolution
- 10 History
- 11 See also
- 12 References
- 13 External links
Nuclear receptors are specific to metazoans (animals) and are not found in protists, algae, fungi, or plants. Amongst the early-branching animal lineages with sequenced genomes, two have been reported from the sponge Amphimedon queenslandica, two from the ctenophore Mnemiopsis leidyi four from the placozoan Trichoplax adhaerens and 17 from the cnidarian Nematostella vectensis. There are 270 nuclear receptors in the nematode C. elegans alone, 21 in D. melanogaster and other insects, 73 in zebrafish. Humans, mice, and rats have respectively 48, 49, and 47 nuclear receptors each.
Ligands that bind to and activate nuclear receptors include lipophilic substances such as endogenous hormones, vitamins A and D, and xenobiotic endocrine disruptors. Because the expression of a large number of genes is regulated by nuclear receptors, ligands that activate these receptors can have profound effects on the organism. Many of these regulated genes are associated with various diseases, which explains why the molecular targets of approximately 13% of U.S. Food and Drug Administration (FDA) approved drugs target nuclear receptors.
A number of nuclear receptors, referred to as orphan receptors, have no known (or at least generally agreed upon) endogenous ligands. Some of these receptors such as FXR, LXR, and PPAR bind a number of metabolic intermediates such as fatty acids, bile acids and/or sterols with relatively low affinity. These receptors hence may function as metabolic sensors. Other nuclear receptors, such as CAR and PXR appear to function as xenobiotic sensors up-regulating the expression of cytochrome P450 enzymes that metabolize these xenobiotics.
This section is missing information about active/inactive LBD; α10 kink.August 2019)(
- (A-B) N-terminal regulatory domain: Contains the activation function 1 (AF-1) whose action is independent of the presence of ligand. The transcriptional activation of AF-1 is normally very weak, but it does synergize with AF-2 in the E-domain (see below) to produce a more robust upregulation of gene expression. The A-B domain is highly variable in sequence between various nuclear receptors.
- (C) DNA-binding domain (DBD): Highly conserved domain containing two zinc fingers that binds to specific sequences of DNA called hormone response elements (HRE).
- (D) Hinge region: Thought to be a flexible domain that connects the DBD with the LBD. Influences intracellular trafficking and subcellular distribution with a target peptide sequence.
- (E) Ligand binding domain (LBD): Moderately conserved in sequence and highly conserved in structure between the various nuclear receptors. The structure of the LBD is referred to as an alpha helical sandwich fold in which three anti parallel alpha helices (the "sandwich filling") are flanked by two alpha helices on one side and three on the other (the "bread"). The ligand binding cavity is within the interior of the LBD and just below three anti parallel alpha helical sandwich "filling". Along with the DBD, the LBD contributes to the dimerization interface of the receptor and in addition, binds coactivator and corepressor proteins. The LBD also contains the activation function 2 (AF-2) whose action is dependent on the presence of bound ligand, controlled by the conformation of helix 12 (H12).
- (F) C-terminal domain: Highly variable in sequence between various nuclear receptors.
The N-terminal (A/B), DNA-binding (C), and ligand binding (E) domains are independently well folded and structurally stable while the hinge region (D) and optional C-terminal (F) domains may be conformationally flexible and disordered. 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), one binding on DR4 (by 4 bp).
Mechanism of action
Nuclear receptors are multifunctional proteins that transduce signals of their cognate 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.
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. 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.
Ligand binding to type I nuclear receptors in the cytosol results in the dissociation of heat shock proteins, homo-dimerization, translocation (i.e., active transport) from the cytoplasm into the cell nucleus, and binding to specific sequences of DNA known as hormone response elements (HREs). Type I nuclear receptors bind to HREs consisting of two half-sites separated by a variable length of DNA, and the second half-site has a sequence inverted from the first (inverted repeat). Type I nuclear receptors include members of subfamily 3, such as the androgen receptor, estrogen receptors, glucocorticoid receptor, and progesterone receptor.
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 receptors, as their endogenous ligands are still unknown.
Type II receptors, in contrast to type I, are retained in the nucleus regardless of the ligand binding status and in addition bind as hetero-dimers (usually with RXR) to DNA. In the absence of ligand, type II nuclear receptors are often complexed with corepressor proteins. Ligand binding to the nuclear receptor causes dissociation of corepressor and recruitment of coactivator proteins. Additional proteins including RNA polymerase are then recruited to the NR/DNA complex that transcribe DNA into messenger RNA.
Type 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 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.
Nuclear receptors bound to hormone response elements recruit a significant number of other proteins (referred to as transcription coregulators) that facilitate or inhibit the transcription of the associated target gene into mRNA. 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.
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.
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
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.
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).
Other synthetic nuclear receptor ligands have no apparent effect on gene transcription in the absence of endogenous ligand. However they block the effect of agonist through competitive binding to the same binding site in the nuclear receptor. These ligands are referred to as antagonists. An example of antagonistic nuclear receptor drug is mifepristone which binds to the glucocorticoid and progesterone receptors and therefore blocks the activity of the endogenous hormones cortisol and progesterone respectively. Antagonist ligands work by inducing a conformation of the receptor which prevents coactivator and promotes corepressor binding (see lower half of the figure to the right).
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
A number of drugs that work through nuclear receptors display an agonist response in some tissues and an antagonistic response in other tissues. This behavior may have substantial benefits since it may allow retaining the desired beneficial therapeutic effects of a drug while minimizing undesirable side effects. Drugs with this mixed agonist/antagonist profile of action are referred to as selective receptor modulators (SRMs). Examples include Selective Androgen Receptor Modulators (SARMs), Selective Estrogen Receptor Modulators (SERMs) and Selective Progesterone Receptor Modulators (SPRMs). The mechanism of action of SRMs may vary depending on the chemical structure of the ligand and the receptor involved, however it is thought that many SRMs work by promoting a conformation of the receptor that is closely balanced between agonism and antagonism. In tissues where the concentration of coactivator proteins is higher than corepressors, the equilibrium is shifted in the agonist direction. Conversely in tissues where corepressors dominate, the ligand behaves as an antagonist.
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. One example of a nuclear receptor that are able to transrepress is the glucocorticoid receptor (GR). Furthermore, certain GR ligands known as Selective Glucocorticoid Receptor Agonists (SEGRAs) are able to activate GR in such a way that GR more strongly transrepresses than transactivates. This selectivity increases the separation between the desired antiinflammatory effects and undesired metabolic side effects of these selective glucocorticoids.
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.
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. 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 TRÎ² involves the phosphatidylinositol 3-kinase (PI3K). This signaling can be blocked by a single tyrosine to phenylalanine substitution in TRÎ² without disrupting direct gene regulation. When mice were created with this single, conservative amino acid substitution in TRÎ², synaptic maturation and plasticity in the hippocampus was impaired almost as effectively as completely blocking thyroid hormone synthesis. This mechanism appears to be conserved in all mammals but not in TRÎ± or any other nuclear receptors. Thus, phosphotyrosine-dependent association of TRÎ² 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.
The following is a list of the 48 known human nuclear receptors (and their orthologs in other species) categorized according to sequence homology. The list also includes selected family members that lack human orthologs (NRNC symbol highlighted in yellow).
|1||Thyroid Hormone Receptor-like||A||Thyroid hormone receptor||NR1A1||TRÎ±||Thyroid hormone receptor-Î±||THRA||thyroid hormone|
|NR1A2||TRÎ²||Thyroid hormone receptor-Î²||THRB|
|B||Retinoic acid receptor||NR1B1||RARÎ±||Retinoic acid receptor-Î±||RARA||vitamin A and related compounds|
|NR1B2||RARÎ²||Retinoic acid receptor-Î²||RARB|
|NR1B3||RARÎ³||Retinoic acid receptor-Î³||RARG|
|C||Peroxisome proliferator-activated receptor||NR1C1||PPARÎ±||Peroxisome proliferator-activated receptor-Î±||PPARA||fatty acids, prostaglandins|
|NR1C2||PPAR-Î²/Î´||Peroxisome proliferator-activated receptor-Î²/Î´||PPARD|
|NR1C3||PPARÎ³||Peroxisome proliferator-activated receptor-Î³||PPARG|
(arthropod, trematode, mullosc, nematode)
|NR1E1||Eip78C||Ecdysone-induced protein 78C||Eip78C|
|F||RAR-related orphan receptor||NR1F1||RORÎ±||RAR-related orphan receptor-Î±||RORA||cholesterol, ATRA|
|NR1F2||RORÎ²||RAR-related orphan receptor-Î²||RORB|
|NR1F3||RORÎ³||RAR-related orphan receptor-Î³||RORC|
|G||CNR14-like (nematode)||NR1G1||sex-1||Steroid hormone receptor cnr14||sex-1|
|H||Liver X receptor-like||NR1H1||EcR||Ecdysone receptor, EcR (arthropod)||EcR||ecdysteroids|
|NR1H2||LXRÎ²||Liver X receptor-Î²||NR1H2||oxysterols|
|NR1H3||LXRÎ±||Liver X receptor-Î±||NR1H3|
|NR1H4||FXR||Farnesoid X receptor||NR1H4|
|NR1H5||FXR-Î²||Farnesoid X receptor-Î²
(pseudogene in human)
|I||Vitamin D receptor-like||NR1I1||VDR||Vitamin D receptor||VDR||vitamin D|
|NR1I2||PXR||Pregnane X receptor||NR1I2||xenobiotics|
|NR1I3||CAR||Constitutive androstane receptor||NR1I3||androstane|
|J||Hr96-like||NR1J1||Hr96/Daf-12||Nuclear hormone receptor HR96||Hr96||cholestrol/dafachronic acid|
|K||Hr1-like||NR1K1||Hr1||Nuclear hormone receptor HR1|
|2||Retinoid X Receptor-like||A||Hepatocyte nuclear factor-4||NR2A1||HNF4Î±||Hepatocyte nuclear factor-4-Î±||HNF4A||fatty acids|
|NR2A2||HNF4Î³||Hepatocyte nuclear factor-4-Î³||HNF4G|
|B||Retinoid X receptor||NR2B1||RXRÎ±||Retinoid X receptor-Î±||RXRA||retinoids|
|NR2B2||RXRÎ²||Retinoid X receptor-Î²||RXRB|
|NR2B3||RXRÎ³||Retinoid X receptor-Î³||RXRG|
|NR2B4||USP||Ultraspiracle protein (arthropod)||usp||phospholipids|
|C||Testicular receptor||NR2C1||TR2||Testicular receptor 2||NR2C1|
|NR2C2||TR4||Testicular receptor 4||NR2C2|
|E||TLX/PNR||NR2E1||TLX||Homologue of the Drosophila tailless gene||NR2E1|
|NR2E3||PNR||Photoreceptor cell-specific nuclear receptor||NR2E3|
|F||COUP/EAR||NR2F1||COUP-TFI||Chicken ovalbumin upstream promoter-transcription factor I||NR2F1|
|NR2F2||COUP-TFII||Chicken ovalbumin upstream promoter-transcription factor II||NR2F2||retinoic acid (weak)|
|3||Estrogen Receptor-like||A||Estrogen receptor||NR3A1||ERÎ±||Estrogen receptor-Î±||ESR1||estrogens|
|B||Estrogen related receptor||NR3B1||ERRÎ±||Estrogen-related receptor-Î±||ESRRA|
|C||3-Ketosteroid receptors||NR3C1||GR||Glucocorticoid receptor||NR3C1||cortisol|
|4||Nerve Growth Factor IB-like||A||NGFIB/NURR1/NOR1||NR4A1||NGFIB||Nerve Growth factor IB||NR4A1|
|NR4A2||NURR1||Nuclear receptor related 1||NR4A2|
|NR4A3||NOR1||Neuron-derived orphan receptor 1||NR4A3|
|A||SF1/LRH1||NR5A1||SF1||Steroidogenic factor 1||NR5A1||phosphatidylinositols|
|NR5A2||LRH-1||Liver receptor homolog-1||NR5A2||phosphatidylinositols|
|B||Hr39-like||NR5B1||HR39||Nuclear hormone receptor FTZ-F1 beta||Hr39|
|6||Germ Cell Nuclear Factor-like||A||GCNF||NR6A1||GCNF||Germ cell nuclear factor||NR6A1|
|7||NRs with two DNA binding domains
(flatworms, mollusks, arthropods)
|8||NR8 (eumetazoa)||A||NR8A||NR8A1||CgNR8A1||Nuclear receptor 8||AKG49571|
|0||Miscellaneous (lacks either LBD or DBD)||A||knr/knrl/egon (arthropods)||NR0A1||KNI||Zygotic gap protein knirps||knl|
|B||DAX/SHP||NR0B1||DAX1||Dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1||NR0B1|
|NR0B2||SHP||Small heterodimer partner||NR0B2|
Of the two 0-families, 0A has a family 1-like DBD, and 0B has a very 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 an family 0B-like LBD. The placement of C. elegans nhr-1 ( ) is disputed: although most sources place it as NR1K1, manual annotation at WormBase considers it a member of NR2A. There used to be a group 2D for which the only member was Drosophilia HR78/NR1D1 ( ) and orthologues, but it was merged into group 2C later due to high similarity, forming a "group 2C/D". Knockout studies on mice and fruit flies support such a merged group.
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. 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.
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. 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 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.
- 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.
- Orphan receptors are found amongst all six subfamilies of nuclear receptors, while ligand-dependent receptors are found amongst three. 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).
- 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.
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.
- 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 receptors, HNF4 and USP were found, via structural and mass spectrometry analysis, to bind fatty acids and phospholipids respectively.
- 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.
- 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.
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.
Below is a brief selection of key events in the history of nuclear receptor research.
- 1905 â€“ Ernest Starling coined the word hormone
- 1926 â€“ Edward Calvin Kendall and Tadeus Reichstein isolated and determined the structures of cortisone and thyroxine
- 1929 â€“ Adolf Butenandt and Edward Adelbert Doisy â€“ independently isolated and determined the structure of estrogen
- 1958 â€“ Elwood Jensen â€“ isolated the estrogen receptor
- 1980s â€“ cloning of the estrogen, glucocorticoid, and thyroid hormone receptors by Pierre Chambon, Ronald Evans, and BjÃ¶rn VennstrÃ¶m respectively
- 2004 â€“ Pierre Chambon, Ronald Evans, and Elwood Jensen were awarded the Albert Lasker Award for Basic Medical Research, an award that frequently precedes a Nobel Prize in Medicine
- "Structure of the intact PPAR-gamma-RXR- nuclear receptor complex on DNA". Nature. 456 (7220): 350â€“6. doi:10.1038/nature07413. PMC 2743566. PMID 19043829. ; Chandra V, Huang P, Hamuro Y, Raghuram S, Wang Y, Burris TP, Rastinejad F (November 2008).
- Evans RM (May 1988). "The steroid and thyroid hormone receptor superfamily". Science. 240 (4854): 889â€“95. Bibcode:1988Sci...240..889E. doi:10.1126/science.3283939. PMC 6159881. PMID 3283939.
- Olefsky JM (October 2001). "Nuclear receptor minireview series". The Journal of Biological Chemistry. 276 (40): 36863â€“4. doi:10.1074/jbc.R100047200. PMID 11459855.
- Mangelsdorf DJ, Thummel C, Beato M, Herrlich P, SchÃ¼tz G, Umesono K, Blumberg B, Kastner P, Mark M, Chambon P, Evans RM (December 1995). "The nuclear receptor superfamily: the second decade". Cell. 83 (6): 835â€“9. doi:10.1016/0092-8674(95)90199-X. PMC 6159888. PMID 8521507.
- Novac N, Heinzel T (December 2004). "Nuclear receptors: overview and classification". Current Drug Targets. Inflammation and Allergy. 3 (4): 335â€“46. doi:10.2174/1568010042634541. PMID 15584884.
- Nuclear Receptors Nomenclature Committee (April 1999). "A unified nomenclature system for the nuclear receptor superfamily". Cell. 97 (2): 161â€“3. doi:10.1016/S0092-8674(00)80726-6. PMID 10219237.
- Laudet V (December 1997). "Evolution of the nuclear receptor superfamily: early diversification from an ancestral orphan receptor". Journal of Molecular Endocrinology. 19 (3): 207â€“26. doi:10.1677/jme.0.0190207. PMID 9460643.
- Escriva H, Langlois MC, MendonÃ§a RL, Pierce R, Laudet V (May 1998). "Evolution and diversification of the nuclear receptor superfamily". Annals of the New York Academy of Sciences. 839 (1): 143â€“6. Bibcode:1998NYASA.839..143E. doi:10.1111/j.1749-6632.1998.tb10747.x. PMID 9629140.
- Reitzel AM, Pang K, Ryan JF, Mullikin JC, Martindale MQ, Baxevanis AD, Tarrant AM (February 2011). "Nuclear receptors from the ctenophore Mnemiopsis leidyi lack a zinc-finger DNA-binding domain: lineage-specific loss or ancestral condition in the emergence of the nuclear receptor superfamily?". EvoDevo. 2 (1): 3. doi:10.1186/2041-9139-2-3. PMC 3038971. PMID 21291545.
- Bridgham JT, Eick GN, Larroux C, Deshpande K, Harms MJ, Gauthier ME, Ortlund EA, Degnan BM, Thornton JW (October 2010). "Protein evolution by molecular tinkering: diversification of the nuclear receptor superfamily from a ligand-dependent ancestor". PLoS Biology. 8 (10): e1000497. doi:10.1371/journal.pbio.1000497. PMC 2950128. PMID 20957188.
- Sluder AE, Maina CV (April 2001). "Nuclear receptors in nematodes: themes and variations". Trends in Genetics. 17 (4): 206â€“13. doi:10.1016/S0168-9525(01)02242-9. PMID 11275326.
- Cheatle Jarvela AM, Pick L (2017). "The Function and Evolution of Nuclear Receptors in Insect Embryonic Development". Current Topics in Developmental Biology: 39â€“70. doi:10.1016/bs.ctdb.2017.01.003.
- Schaaf MJ (2017). "Nuclear receptor research in zebrafish". Journal of Molecular Endocrinology. 59: R65â€“R76. doi:10.1530/JME-17-0031.
- Zhang Z, Burch PE, Cooney AJ, Lanz RB, Pereira FA, Wu J, Gibbs RA, Weinstock G, Wheeler DA (April 2004). "Genomic analysis of the nuclear receptor family: new insights into structure, regulation, and evolution from the rat genome". Genome Research. 14 (4): 580â€“90. doi:10.1101/gr.2160004. PMC 383302. PMID 15059999.
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- Crossgrove K, Laudet V, Maina CV (February 2002). "Dirofilaria immitis encodes Di-nhr-7, a putative orthologue of the Drosophila ecdysone-regulated E78 gene". Molecular and Biochemical Parasitology. 119 (2): 169â€“77. doi:10.1016/s0166-6851(01)00412-1. PMID 11814569.
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This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.
Ligand-binding domain of nuclear hormone receptor Provide feedback
This all helical domain is involved in binding the hormone in these receptors.
Tanenbaum DM, Wang Y, Williams SP, Sigler PB; , Proc Natl Acad Sci U S A 1998;95:5998-6003.: Crystallographic comparison of the estrogen and progesterone receptor's ligand binding domains. PUBMED:9600906 EPMC:9600906
Internal database links
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR000536
Nuclear receptors (NRs), such as the receptors for steroids and thyroid hormones, retinoids and vitamin D3, are one of the most abundant classes of transcriptional regulators in animals (metazoans). They regulate diverse functions, such as homeostasis, reproduction, development and metabolism. The most prominent feature differentiating them from other transcription factors is their capacity to bind small hydrophobic molecules specifically. These ligands constitute regulatory signals, which modify the NR transcriptional activity through conformational changes. Prototypical NRs share a common structural organization with a variable amino-terminal (Nter) domain that contains a constitutively active activation function (AF)-1, a conserved DNA- binding domain (DBD) consisting of two zinc fingers, a linker region, and a C-terminal (Cter) ligand-binding domain (LBD), also called HOLI domain [PUBMED:12538758, PUBMED:15105832, PUBMED:24844133].
The NR LBD plays a crucial role in ligand-mediated NR activity. In addition to its role is ligand recognition, the LBD also contains a ligand-dependent AF-2. Conformational changes in AF-2 induced by various ligands can modulate interactions with conserved motifs of coregulatory proteins. Specifically, the binding of ligands to the LBD determines the recruiting of transcriptional coregulators which triggers induction or repression of target genes. The coregulators include coactivators like the p160 factors also referred to as the steroid receptor coactivators (SRC) family, and corepressors such as SMART (silencing mediator for retinoid and thyroid hormone receptors) and N-CoR (nuclear corepressor) [PUBMED:24361687, PUBMED:11050318, PUBMED:9640540, PUBMED:20723571].
The overall structure of NR LBD is composed of about 11-13 alpha-helices that are arranged into a three-layer antiparallel alpha-helical sandwich with the three long helices (helices 3, 7, and 10) forming the two outer layers. The middle layer of helices (helices 4, 5, 8 and 9) is present only in the top half of the domain but is missing from the bottom half, thereby creating a cavity, so called ligand-binding pocket, for ligand binding in most receptors. The bound ligands stabilize the NR conformation through direct contacts with multiple structural elements including helices H3, H5, H6, H7, H10, and the loop preceeding the AF-2 helix. The C-terminal activation region also forms an alpha-helix (AF-2), which can adopt multiple conformation depending on the nature of the bound ligand. Helices 3,4 and 12 enclose a shallow hydrophobic groove which is the site for coregulator binding. Despite the conserved fold of NR LBDs, the ligand-binding pocket is the least conserved region among different NR LBDs [PUBMED:11050318, PUBMED:9640540, PUBMED:20723571].
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
The graphic that is shown by default represents the longest sequence with a given architecture. Each row contains the following information:
- the number of sequences which exhibit this architecture
a textual description of the architecture, e.g. Gla, EGF x 2, Trypsin.
This example describes an architecture with one
Gladomain, followed by two consecutive
EGFdomains, and finally a single
- a link to the page in the Pfam site showing information about the sequence that the graphic describes
- the UniProt description of the protein sequence
- the number of residues in the sequence
- the Pfam graphic itself.
Note that you can see the family page for a particular domain by clicking on the graphic. You can also choose to see all sequences which have a given architecture by clicking on the Show link in each row.
Finally, because some families can be found in a very large number of architectures, we load only the first fifty architectures by default. If you want to see more architectures, click the button at the bottom of the page to load the next set.
Loading domain graphics...
We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database (reference proteomes) using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the UniProtKB sequence database, the NCBI sequence database, and our metagenomics sequence database. More...
There are various ways to view or download the sequence alignments that we store. We provide several sequence viewers and a plain-text Stockholm-format file for download.
We make a range of alignments for each Pfam-A family:
- the curated alignment from which the HMM for the family is built
- the alignment generated by searching the sequence database using the HMM
- Representative Proteomes (RPs) at 15%, 35%, 55% and 75% co-membership thresholds
- alignment generated by searching the UniProtKB sequence database using the family HMM
- alignment generated by searching the NCBI sequence database using the family HMM
- alignment generated by searching the metagenomics sequence database using the family HMM
You can see the alignments as HTML or in three different sequence viewers:
- a Java applet developed at the University of Dundee. You will need Java installed before running jalview
- an HTML page showing the whole alignment.Please note: full Pfam alignments can be very large. These HTML views are extremely large and often cause problems for browsers. Please use either jalview or the Pfam viewer if you have trouble viewing the HTML version
- an HTML-based representation of the alignment, coloured according to the posterior-probability (PP) values from the HMM. As for the standard HTML view, heatmap alignments can also be very large and slow to render.
You can download (or view in your browser) a text representation of a Pfam alignment in various formats:
You can also change the order in which sequences are listed in the alignment, change how insertions are represented, alter the characters that are used to represent gaps in sequences and, finally, choose whether to download the alignment or to view it in your browser directly.
You may find that large alignments cause problems for the viewers and the reformatting tool, so we also provide all alignments in Stockholm format. You can download either the plain text alignment, or a gzipped version of it.
We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.
1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
Format an alignment
We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.
You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.
HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...
If you find these logos useful in your own work, please consider citing the following article:
This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.
Note: You can also download the data file for the tree.
Curation and family details
This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.
|Author:||Sonnhammer ELL , Griffiths-Jones SR , Bateman A|
|Number in seed:||337|
|Number in full:||14256|
|Average length of the domain:||179.80 aa|
|Average identity of full alignment:||18 %|
|Average coverage of the sequence by the domain:||38.66 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 45638612 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||30|
|Download:||download the raw HMM for this family|
Weight segments by...
Change the size of the sunburst
selected sequences to HMM
a FASTA-format file
- 0 sequences
- 0 species
This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the More....
This chart is a modified "sunburst" visualisation of the species tree for this family. It shows each node in the tree as a separate arc, arranged radially with the superkingdoms at the centre and the species arrayed around the outermost ring.
How the sunburst is generated
The tree is built by considering the taxonomic lineage of each sequence that has a match to this family. For each node in the resulting tree, we draw an arc in the sunburst. The radius of the arc, its distance from the root node at the centre of the sunburst, shows the taxonomic level ("superkingdom", "kingdom", etc). The length of the arc represents either the number of sequences represented at a given level, or the number of species that are found beneath the node in the tree. The weighting scheme can be changed using the sunburst controls.
In order to reduce the complexity of the representation, we reduce the number of taxonomic levels that we show. We consider only the following eight major taxonomic levels:
Colouring and labels
Segments of the tree are coloured approximately according to their superkingdom. For example, archeal branches are coloured with shades of orange, eukaryotes in shades of purple, etc. The colour assignments are shown under the sunburst controls. Where space allows, the name of the taxonomic level will be written on the arc itself.
As you move your mouse across the sunburst, the current node will be highlighted. In the top section of the controls panel we show a summary of the lineage of the currently highlighed node. If you pause over an arc, a tooltip will be shown, giving the name of the taxonomic level in the title and a summary of the number of sequences and species below that node in the tree.
Anomalies in the taxonomy tree
There are some situations that the sunburst tree cannot easily handle and for which we have work-arounds in place.
Missing taxonomic levels
Some species in the taxonomic tree may not have one or more of the main eight levels that we display. For example, Bos taurus is not assigned an order in the NCBI taxonomic tree. In such cases we mark the omitted level with, for example, "No order", in both the tooltip and the lineage summary.
Unmapped species names
The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
So that these nodes are not simply omitted from the sunburst tree, we group them together in a separate branch (or segment of the sunburst tree). Since we cannot determine the lineage for these unmapped species, we show all levels between the superkingdom and the species as "uncategorised".
Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.
Too many species/sequences
For large species trees, you may see blank regions in the outer layers of the sunburst. These occur when there are large numbers of arcs to be drawn in a small space. If an arc is less than approximately one pixel wide, it will not be drawn and the space will be left blank. You may still be able to get some information about the species in that region by moving your mouse across the area, but since each arc will be very small, it will be difficult to accurately locate a particular species.
The tree shows the occurrence of this domain across different species. More...
We show the species tree in one of two ways. For smaller trees we try to show an interactive representation, which allows you to select specific nodes in the tree and view them as an alignment or as a set of Pfam domain graphics.
Unfortunately we have found that there are problems viewing the interactive tree when the it becomes larger than a certain limit. Furthermore, we have found that Internet Explorer can become unresponsive when viewing some trees, regardless of their size. We therefore show a text representation of the species tree when the size is above a certain limit or if you are using Internet Explorer to view the site.
If you are using IE you can still load the interactive tree by clicking the "Generate interactive tree" button, but please be aware of the potential problems that the interactive species tree can cause.
For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.
Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.
We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
You can use the tree controls to manipulate how the interactive tree is displayed:
- show/hide the summary boxes
- highlight species that are represented in the seed alignment
- expand/collapse the tree or expand it to a given depth
- select a sub-tree or a set of species within the tree and view them graphically or as an alignment
- save a plain text representation of the tree
Please note: for large trees this can take some time. While the tree is loading, you can safely switch away from this tab but if you browse away from the family page entirely, the tree will not be loaded.
There are 8 interactions for this family. More...
We determine these interactions using iPfam, which considers the interactions between residues in three-dimensional protein structures and maps those interactions back to Pfam families. You can find more information about the iPfam algorithm in the journal article that accompanies the website.
For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Hormone_recep domain has been found. There are 2097 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.
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