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2757  structures 482  species 0  interactions 32199  sequences 273  architectures

Family: Hormone_recep (PF00104)

Summary: Ligand-binding domain of nuclear hormone receptor

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This is the Wikipedia entry entitled "Nuclear receptor". More...

Nuclear receptor Edit Wikipedia article

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

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

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

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

Species distribution

Nuclear receptors are specific to metazoans (animals) and are not found in protists, algae, fungi, or plants.[8] Amongst the early-branching animal lineages with sequenced genomes, two have been reported from the sponge Amphimedon queenslandica, two from the ctenophore Mnemiopsis leidyi[9] four from the placozoan Trichoplax adhaerens and 17 from the cnidarian Nematostella vectensis.[10] There are 270 nuclear receptors in the nematode C. elegans alone,[11] 21 in D. melanogaster and other insects,[12] 73 in zebrafish.[13] Humans, mice, and rats have respectively 48, 49, and 47 nuclear receptors each.[14]


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

Ligands that bind to and activate nuclear receptors include lipophilic substances such as endogenous hormones, vitamins A and D, and xenobiotic endocrine disruptors. Because the expression of a large number of genes is regulated by nuclear receptors, ligands that activate these receptors can have profound effects on the organism. Many of these regulated genes are associated with various diseases, which explains why the molecular targets of approximately 13% of U.S. Food and Drug Administration (FDA) approved drugs target nuclear receptors.[15]

A number of nuclear receptors, referred to as orphan receptors,[16] 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.[17]


Most nuclear receptors have molecular masses between 50,000 and 100,000 daltons.

Nuclear receptors are modular in structure and contain the following domains:[18][19]

  • (A-B) N-terminal regulatory domain: Contains the activation function 1 (AF-1) whose action is independent of the presence of ligand.[20] 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).[20]
  • (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.[21] 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),[1][22] one binding on DR4 (by 4 bp).[23]

Structural Organization of Nuclear Receptors
Top – Schematic 1D amino acid sequence of a nuclear receptor.
Bottom – 3D structures of the DBD (bound to DNA) and LBD (bound to hormone) regions of the nuclear receptor. The structures shown are of the estrogen receptor. Experimental structures of N-terminal domain (A/B), hinge region (D), and C-terminal domain (F) have not been determined therefore are represented by red, purple, and orange dashed lines, respectively.
DNA binding domain (DBD)
PR DBD 2C7A.png
Crystallographic structure of the human progesterone receptor DNA-binding domain dimer (cyan and green) complexed with double stranded DNA (magenta). Zinc atoms of are depicted as grey spheres.[24]
Ligand-binding domain (LBD)
RORC 3L0L.png
Crystallographic structure of the ligand binding domain of the human RORγ (rainbow colored, N-terminus = blue, C-terminus = red) complexed with 25-hydroxycholesterol (space-filling model (carbon = white, oxygen = red) and the NCOA2 coactivator (magneta).[25]

Mechanism of action

Mechanism of class I nuclear receptor action. A class I nuclear receptor (NR), in the absence of ligand, is located in the cytosol. Hormone binding to the NR triggers dissociation of heat shock proteins (HSP), dimerization, and translocation to the nucleus, where the NR binds to a specific sequence of DNA known as a hormone response element (HRE). The nuclear receptor DNA complex in turn recruits other proteins that are responsible for transcription of downstream DNA into mRNA, which is eventually translated into protein, which results in a change in cell function.
Mechanism of class II nuclear receptor action. A class II nuclear receptor (NR), regardless of ligand-binding status, is located in the nucleus bound to DNA. For the purpose of illustration, the nuclear receptor shown here is the thyroid hormone receptor (TR) heterodimerized to the RXR. In the absence of ligand, the TR is bound to corepressor protein. Ligand binding to TR causes a dissociation of corepressor and recruitment of coactivator protein, which, in turn, recruits additional proteins such as RNA polymerase that are responsible for transcription of downstream DNA into RNA and eventually protein.

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.[26] 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.[4]

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

Type I

Ligand binding to type I nuclear receptors in the cytosol results in the dissociation of heat shock proteins, homo-dimerization, translocation (i.e., active transport) from the cytoplasm into the cell nucleus, and binding to specific sequences of DNA known as hormone response elements (HREs). Type I nuclear receptors bind to HREs consisting of two half-sites separated by a variable length of DNA, and the second half-site has a sequence inverted from the first (inverted repeat). Type I nuclear receptors include members of subfamily 3, such as the androgen receptor, estrogen receptors, glucocorticoid receptor, and progesterone receptor.[27]

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.

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

Type II

Type II receptors, in contrast to type I, are retained in the nucleus regardless of the ligand binding status and in addition bind as hetero-dimers (usually with RXR) to DNA.[26] In the absence of ligand, type II nuclear receptors are often complexed with corepressor proteins. Ligand binding to the nuclear receptor causes dissociation of corepressor and recruitment of coactivator proteins. Additional proteins including RNA polymerase are then recruited to the NR/DNA complex that transcribe DNA into messenger RNA.

Type II nuclear receptors include principally subfamily 1, for example the retinoic acid receptor, retinoid X receptor and thyroid hormone receptor.[28]

Type III

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

Type IV

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

Coregulatory proteins

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.[29][30] 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.[31]


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

Structural basis for the mechanism of nuclear receptor agonist and antagonist action.[32] The structures shown here are of the ligand binding domain (LBD) of the estrogen receptor (green cartoon diagram) complexed with either the agonist diethylstilbestrol (top, PDB: 3ERD​) or antagonist 4-hydroxytamoxifen (bottom, 3ERT​). The ligands are depicted as space filling spheres (white = carbon, red = oxygen). When an agonist is bound to a nuclear receptor, the C-terminal alpha helix of the LDB (H12; light blue) is positioned such that a coactivator protein (red) can bind to the surface of the LBD. Shown here is just a small part of the coactivator protein, the so-called NR box containing the LXXLL amino acid sequence motif.[33] Antagonists occupy the same ligand binding cavity of the nuclear receptor. However antagonist ligands in addition have a sidechain extension which sterically displaces H12 to occupy roughly the same position in space as coactivators bind. Hence coactivator binding to the LBD is blocked.

Depending on the receptor involved, the chemical structure of the ligand and the tissue that is being affected, nuclear receptor ligands may display dramatically diverse effects ranging in a spectrum from agonism to antagonism to inverse agonism.[34]


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).

Inverse agonists

Finally, some nuclear receptors promote a low level of gene transcription in the absence of agonists (also referred to as basal or constitutive activity). Synthetic ligands which reduce this basal level of activity in nuclear receptors are known as inverse agonists.[35]

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.[36]

Alternative mechanisms

Phylogenetic tree of human nuclear receptors


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.[37] 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.[38][39]

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.[40][41] 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 TRβ involves the phosphatidylinositol 3-kinase (PI3K).[42] This signaling can be blocked by a single tyrosine to phenylalanine substitution in TRβ without disrupting direct gene regulation.[43] When mice were created with this single, conservative amino acid substitution in TRβ,[43] synaptic maturation and plasticity in the hippocampus was impaired almost as effectively as completely blocking thyroid hormone synthesis.[44] This mechanism appears to be conserved in all mammals but not in TRα or any other nuclear receptors. Thus, phosphotyrosine-dependent association of TRβ with PI3K provides a potential mechanism for integrating regulation of development and metabolism by thyroid hormone and receptor tyrosine kinases. In addition, thyroid hormone signaling through PI3K can alter gene expression.[45]

Family members

The following is a list of the 48 known human nuclear receptors (and their orthologs in other species)[14][46] categorized according to sequence homology.[6][7] The list also includes selected family members that lack human orthologs (NRNC symbol highlighted in yellow).

Subfamily Group Member
NRNC Symbol[6] Abbreviation Name Gene Ligand(s)
1 Thyroid Hormone Receptor-like A Thyroid hormone receptor NR1A1 TRα Thyroid hormone receptor-α THRA thyroid hormone
NR1A2 TRβ Thyroid hormone receptor-β THRB
B Retinoic acid receptor NR1B1 RARα Retinoic acid receptor-α RARA vitamin A and related compounds
NR1B2 RARβ Retinoic acid receptor-β RARB
NR1B3 RARγ Retinoic acid receptor-γ RARG
C Peroxisome proliferator-activated receptor NR1C1 PPARα Peroxisome proliferator-activated receptor-α PPARA fatty acids, prostaglandins
NR1C2 PPAR-β/δ Peroxisome proliferator-activated receptor-β/δ PPARD
NR1C3 PPARγ Peroxisome proliferator-activated receptor-γ PPARG
D Rev-ErbA NR1D1 Rev-ErbAα Rev-ErbAα NR1D1 heme
NR1D2 Rev-ErbAβ Rev-ErbAα NR1D2
E E78C-like
(arthropod, trematode, mullosc, nematode)[46][47]
NR1E1 Eip78C Ecdysone-induced protein 78C Eip78C
F RAR-related orphan receptor NR1F1 RORα RAR-related orphan receptor-α RORA cholesterol, ATRA
NR1F2 RORβ RAR-related orphan receptor-β RORB
NR1F3 RORγ RAR-related orphan receptor-γ RORC
G CNR14-like (nematode)[46] NR1G1 sex-1 Steroid hormone receptor cnr14[48] sex-1
H Liver X receptor-like NR1H1 EcR Ecdysone receptor, EcR (arthropod) EcR ecdysteroids
NR1H2 LXRβ Liver X receptor-β NR1H2 oxysterols
NR1H3 LXRα Liver X receptor-α NR1H3
NR1H4 FXR Farnesoid X receptor NR1H4
NR1H5[49] FXR-β Farnesoid X receptor-β
(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[46] NR1J1 Hr96/Daf-12 Nuclear hormone receptor HR96 Hr96 cholestrol/dafachronic acid[50]
K Hr1-like[46] NR1K1 Hr1 Nuclear hormone receptor HR1
2 Retinoid X Receptor-like A Hepatocyte nuclear factor-4 NR2A1 HNF4α Hepatocyte nuclear factor-4-α HNF4A fatty acids
NR2A2 HNF4γ Hepatocyte nuclear factor-4-γ HNF4G
B Retinoid X receptor NR2B1 RXRα Retinoid X receptor-α RXRA retinoids
NR2B2 RXRβ Retinoid X receptor-β RXRB
NR2B3 RXRγ Retinoid X receptor-γ RXRG
NR2B4 USP Ultraspiracle protein (arthropod) usp phospholipids[51]
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)[52]
NR2F6 EAR-2 V-erbA-related NR2F6
3 Estrogen Receptor-like A Estrogen receptor NR3A1 ERα Estrogen receptor-α ESR1 estrogens
NR3A2 ERβ Estrogen receptor-β ESR2
B Estrogen related receptor NR3B1 ERRα Estrogen-related receptor-α ESRRA
NR3B2 ERRβ Estrogen-related receptor-β ESRRB
NR3B3 ERRγ Estrogen-related receptor-γ ESRRG
C 3-Ketosteroid receptors NR3C1 GR Glucocorticoid receptor NR3C1 cortisol
NR3C2 MR Mineralocorticoid receptor NR3C2 aldosterone
NR3C3 PR Progesterone receptor PGR progesterone
NR3C4 AR Androgen receptor AR testosterone
D Estrogen Receptor-like
(in lophotrochozoa)
E Estrogen Receptor-like
(in cnidaria)[53]
F Estrogen Receptor-like
(in placozoa)
4 Nerve Growth Factor IB-like A NGFIB/NURR1/NOR1 NR4A1 NGFIB Nerve Growth factor IB NR4A1
NR4A2 NURR1 Nuclear receptor related 1 NR4A2
NR4A3 NOR1 Neuron-derived orphan receptor 1 NR4A3
5 Steroidogenic
A SF1/LRH1 NR5A1 SF1 Steroidogenic factor 1 NR5A1 phosphatidylinositols
NR5A2 LRH-1 Liver receptor homolog-1 NR5A2 phosphatidylinositols
B Hr39-like NR5B1[46] 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[46][54]
(flatworms, mollusks, arthropods)
C 2DBD-NRγ NR7C1 arthropod "α/β"  
8 NR8[55] (eumetazoa) A NR8A NR8A1 CgNR8A1 Nuclear receptor 8 AKG49571
0 Miscellaneous (lacks either LBD or DBD) A knr/knrl/egon[46] (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.[46] The placement of C. elegans nhr-1 (Q21878) is disputed: although most sources place it as NR1K1,[46] manual annotation at WormBase considers it a member of NR2A.[56] There used to be a group 2D for which the only member was Drosophilia HR78/NR1D1 (Q24142) and orthologues, but it was merged into group 2C later due to high similarity, forming a "group 2C/D".[46] Knockout studies on mice and fruit flies support such a merged group.[57]


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.[58] 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.[59]

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.[60] 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[7] This hypothesis was proposed based on the following arguments:

  1. 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.[61]
  2. 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.[62]
  3. Orphan receptors are found amongst all six subfamilies of nuclear receptors, while ligand-dependent receptors are found amongst three.[7] 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.
  4. 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).[62]
  5. 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.[62]

Over the next 10 years, experiments were conducted to test this hypothesis and counterarguments soon emerged:

  1. 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.[63]
  2. 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.
  3. Two putative orphan receptors, HNF4 and USP were found, via structural and mass spectrometry analysis, to bind fatty acids and phospholipids respectively.[51]
  4. 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.[64]
  5. 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.[65]

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.[64]


Below is a brief selection of key events in the history of nuclear receptor research.[66]

See also


  1. ^ a b PDB: 3E00​; Chandra V, Huang P, Hamuro Y, Raghuram S, Wang Y, Burris TP, Rastinejad F (November 2008). "Structure of the intact PPAR-gamma-RXR- nuclear receptor complex on DNA". Nature. 456 (7220): 350–6. doi:10.1038/nature07413. PMC 2743566. PMID 19043829.
  2. ^ Evans RM (May 1988). "The steroid and thyroid hormone receptor superfamily". Science. 240 (4854): 889–95. Bibcode:1988Sci...240..889E. doi:10.1126/science.3283939. PMC 6159881. PMID 3283939.
  3. ^ Olefsky JM (October 2001). "Nuclear receptor minireview series". The Journal of Biological Chemistry. 276 (40): 36863–4. doi:10.1074/jbc.R100047200. PMID 11459855.
  4. ^ a b c Mangelsdorf DJ, Thummel C, Beato M, Herrlich P, Schütz 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): 835–9. doi:10.1016/0092-8674(95)90199-X. PMC 6159888. PMID 8521507.
  5. ^ a b Novac N, Heinzel T (December 2004). "Nuclear receptors: overview and classification". Current Drug Targets. Inflammation and Allergy. 3 (4): 335–46. doi:10.2174/1568010042634541. PMID 15584884.
  6. ^ a b c Nuclear Receptors Nomenclature Committee (April 1999). "A unified nomenclature system for the nuclear receptor superfamily". Cell. 97 (2): 161–3. doi:10.1016/S0092-8674(00)80726-6. PMID 10219237.
  7. ^ a b c d Laudet V (December 1997). "Evolution of the nuclear receptor superfamily: early diversification from an ancestral orphan receptor". Journal of Molecular Endocrinology. 19 (3): 207–26. doi:10.1677/jme.0.0190207. PMID 9460643.
  8. ^ Escriva H, Langlois MC, Mendonça 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): 143–6. Bibcode:1998NYASA.839..143E. doi:10.1111/j.1749-6632.1998.tb10747.x. PMID 9629140.
  9. ^ Reitzel AM, Pang K, Ryan JF, Mullikin JC, Martindale MQ, Baxevanis AD, Tarrant AM (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.
  10. ^ 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.
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External links

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

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.

Literature references

  1. 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 organisation with a variable N-terminal 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 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 proceeding 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 ].

Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

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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 and the UniProtKB sequence database. More...

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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.

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You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

HMM logo

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...


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.

Curation View help on the curation process

Seed source: Prosite
Previous IDs: hormone_rec;
Type: Domain
Sequence Ontology: SO:0000417
Author: Sonnhammer ELL , Griffiths-Jones SR , Bateman A
Number in seed: 315
Number in full: 32199
Average length of the domain: 180.40 aa
Average identity of full alignment: 22 %
Average coverage of the sequence by the domain: 37.52 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 61295632 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 23.5 23.5
Trusted cut-off 23.5 23.5
Noise cut-off 23.4 23.4
Model length: 213
Family (HMM) version: 33
Download: download the raw HMM for this family

Species distribution

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Colour assignments

Archea Archea Eukaryota Eukaryota
Bacteria Bacteria Other sequences Other sequences
Viruses Viruses Unclassified Unclassified
Viroids Viroids Unclassified sequence Unclassified sequence


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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 2757 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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AlphaFold Structure Predictions

The list of proteins below match this family and have AlphaFold predicted structures. Click on the protein accession to view the predicted structure.

Protein Predicted structure External Information
A0A0G2JW78 View 3D Structure Click here
A0A0G2JXJ1 View 3D Structure Click here
A0A0G2KE76 View 3D Structure Click here
A0A0G2QC01 View 3D Structure Click here
A0A0K3AVS8 View 3D Structure Click here
A0A0R4IC41 View 3D Structure Click here
A0A0R4IFS6 View 3D Structure Click here
A0A0R4IJK6 View 3D Structure Click here
A0A0R4IVP0 View 3D Structure Click here
A0A131MB42 View 3D Structure Click here
A0A131MBQ7 View 3D Structure Click here
A0A131MCX9 View 3D Structure Click here
A0A2R8Q5W6 View 3D Structure Click here
A0A2R8Q7M6 View 3D Structure Click here
A0A2R8QJZ8 View 3D Structure Click here
A0A2R8QN75 View 3D Structure Click here
A0A2R8QR22 View 3D Structure Click here
A1ZA01 View 3D Structure Click here
A2T928 View 3D Structure Click here
A2T929 View 3D Structure Click here
A2V8C5 View 3D Structure Click here
A4GT83 View 3D Structure Click here
A5JYV4 View 3D Structure Click here
A6YIH7 View 3D Structure Click here
A7LPI6 View 3D Structure Click here
A9C4A5 View 3D Structure Click here
B0S5T9 View 3D Structure Click here
B0V1H8 View 3D Structure Click here
B0V3V6 View 3D Structure Click here
B1GRK7 View 3D Structure Click here
B3DGQ7 View 3D Structure Click here
B3DKN2 View 3D Structure Click here
B3WFU1 View 3D Structure Click here
B8A510 View 3D Structure Click here
B8JJ08 View 3D Structure Click here
B8JJL4 View 3D Structure Click here
D3ZFA7 View 3D Structure Click here
D3ZFD9 View 3D Structure Click here
D3ZWV0 View 3D Structure Click here
E9PSV7 View 3D Structure Click here