Nuclear receptor

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

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

Nuclear receptors have the ability to directly bind to DNA and regulate the expression of adjacent genes; hence these receptors are classified as transcription factors.[2][3] The regulation of gene expression by nuclear receptors generally only happens when a ligand—a molecule that affects the receptor's behavior—is present. More specifically, ligand binding to a nuclear receptor results in a conformational change in the receptor, which, in turn, activates the receptor, resulting in up- 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 comb jelly Mnemiopsis leidyi[9] four from the placozoan Trichoplax adhaerens and 17 from the cnidarian Nematostella vectensis.[10] There are 270 nuclear receptors in the roundworm Caenorhabditis elegans alone,[11] 21 in the fruit fly and other insects,[12] 73 in zebrafish.[13] Humans, mice, and rats have respectively 48, 49, and 47 nuclear receptors each.[14]

Ligands

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

Ligands that bind to and activate nuclear receptors include lipophilic substances such as endogenous hormones, vitamins A and D, and xenobiotic hormones. 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]

Structure

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). Recently, a novel zinc finger motif (CHC2) is identified in parasitic flatworm NRs. [21]
  • (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.[22] 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][23] one binding on DR4 (by 4 bp).[24]

Structural Organization of Nuclear Receptors
Top – Schematic 1D amino acid sequence of a nuclear receptor.
Bottom – 3D structures of the DBD (bound to DNA) and LBD (bound to hormone) regions of the nuclear receptor. The structures shown are of the estrogen receptor. Experimental structures of N-terminal domain (A/B), hinge region (D), and C-terminal domain (F) have not been determined therefore are represented by red, purple, and orange dashed lines, respectively.
DNA binding domain (DBD)
Crystallographic structure of the human progesterone receptor DNA-binding domain dimer (cyan and green) complexed with double stranded DNA (magenta). Zinc atoms of are depicted as grey spheres.[25]
Identifiers
Symbolzf-C4
PfamPF00105
InterProIPR001628
SMARTSM00399
PROSITEPDOC00031
SCOP21hra / SCOPe / SUPFAM
CDDcd06916
Ligand-binding domain (LBD)
Crystallographic structure of the ligand binding domain of the human RORγ (rainbow colored, N-terminus = blue, C-terminus = red) complexed with 25-hydroxycholesterol (space-filling model (carbon = white, oxygen = red) and the NCOA2 coactivator (magneta).[26]
Identifiers
SymbolHormone_recep
PfamPF00104
InterProIPR000536
SMARTSM00430
SCOP21lbd / SCOPe / SUPFAM
CDDcd06157

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.[27] 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.[28]

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.[27] 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.[29]

Type III

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

Type IV

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

Dimerization

Human Nuclear Receptors are capable of dimerizing with many other Nuclear Receptors (homotypic dimerization), as has been shown from large-scale Y2H experiments and text mining efforts of the literature that were focused on specific interactions.[30][31][27] Nevertheless, there exists specificity, with members of the same subfamily having very similar NR dimerization partners and the underlying dimerization network has certain topological features, such as the presence of highly connected hubs (RXR and SHP).[27]

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.[32][33] 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.[34]

Coactivators

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

Corepressors

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

Agonism vs antagonism

Structural basis for the mechanism of nuclear receptor agonist and antagonist action.[35] 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.[36] 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.[37]

Agonists

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

Antagonists

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

Inverse agonists

Finally, some nuclear receptors promote a low level of gene transcription in the absence of agonists (also referred to as basal or constitutive activity). Synthetic ligands which reduce this basal level of activity in nuclear receptors are known as inverse agonists.[38]

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.[39]

Alternative mechanisms

Phylogenetic tree of human nuclear receptors

Transrepression

The most common mechanism of nuclear receptor action involves direct binding of the nuclear receptor to a DNA hormone response element. This mechanism is referred to as transactivation. However some nuclear receptors not only have the ability to directly bind to DNA, but also to other transcription factors. This binding often results in deactivation of the second transcription factor in a process known as transrepression.[40] One example of a nuclear receptor that are able to transrepress is the glucocorticoid receptor (GR). Furthermore, certain GR ligands known as Selective Glucocorticoid Receptor Agonists (SEGRAs) are able to activate GR in such a way that GR more strongly transrepresses than transactivates. This selectivity increases the separation between the desired antiinflammatory effects and undesired metabolic side effects of these selective glucocorticoids.

Non-genomic

The classical direct effects of nuclear receptors on gene regulation normally 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.[41][42]

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.[43][44] 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).[45] This signaling can be blocked by a single tyrosine to phenylalanine substitution in TRβ without disrupting direct gene regulation.[46] When mice were created with this single, conservative amino acid substitution in TRβ,[46] synaptic maturation and plasticity in the hippocampus was impaired almost as effectively as completely blocking thyroid hormone synthesis.[47] 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.[48]

Family members

The following is a list of the 48 known human nuclear receptors (and their orthologs in other species)[14][49] 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)[49][50]		 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)[49] NR1G1 sex-1 Steroid hormone receptor cnr14[51] 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[52] FXR-β Farnesoid X receptor-β
(pseudogene in human)		 NR1H5P
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[49] NR1J1 Hr96/Daf-12 Nuclear hormone receptor HR96 Hr96 cholestrol/dafachronic acid[53]
NR1J2
NR1J3
K Hr1-like[49] 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[54]
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)[55]
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)[56]		 NR3D
E Estrogen Receptor-like
(in cnidaria)[57]		 NR3E
F Estrogen Receptor-like
(in placozoa)[57]		 NR3F
4 Nerve Growth Factor IB-like A NGFIB/NURR1/NOR1 NR4A1 NGFIB Nerve Growth factor IB NR4A1
NR4A2 NURR1 Nuclear receptor related 1 NR4A2
NR4A3 NOR1 Neuron-derived orphan receptor 1 NR4A3
5 Steroidogenic
Factor-like		 A SF1/LRH1 NR5A1 SF1 Steroidogenic factor 1 NR5A1 phosphatidylinositols
NR5A2 LRH-1 Liver receptor homolog-1 NR5A2 phosphatidylinositols
B Hr39-like NR5B1[49] HR39/FTZ-F1 Nuclear hormone receptor fushi tarazu factor I beta Hr39
6 Germ Cell Nuclear Factor-like A GCNF NR6A1 GCNF Germ cell nuclear factor NR6A1
7 NRs with two DNA binding domains[49][58]
(flatworms, mollusks, arthropods)		 A2DBD-NRα NR7A1 
B2DBD-NRβ NR7B1
C2DBD-NRγ NR7C1arthropod "α/β"  
8 NR8[59] (eumetazoa) A NR8A NR8A1 CgNR8A1 Nuclear receptor 8 AKG49571
0 Miscellaneous (lacks either LBD or DBD) A knr/knrl/egon[49] (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.[49] The placement of C. elegans nhr-1 (Q21878) is disputed: although most sources place it as NR1K1,[49] manual annotation at WormBase considers it a member of NR2A.[60] There used to be a group 2D for which the only member was Drosophila HR78/NR1D1 (Q24142) and orthologues, but it was merged into group 2C later due to high similarity, forming a "group 2C/D".[49] Knockout studies on mice and fruit flies support such a merged group.[61]

Evolution

A topic of debate has been on the identity of the ancestral nuclear receptor as either a ligand-binding or an orphan receptor. This debate began more than twenty-five years ago when the first ligands were identified as mammalian steroid and thyroid hormones.[62] 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.[63]

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.[64] 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.[65]
  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.[66]
  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).[66]
  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.[66]

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.[67]
  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.[54]
  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.[68]
  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.[69]

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.[68]

History

Below is a brief selection of key events in the history of nuclear receptor research.[70]

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

See also

  • NucleaRDB
  • Thyroid hormone receptor
  • Steroid hormone receptor
  • Receptors

References

  1. 1 2 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. S2CID 5497175.
  4. 1 2 3 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. 1 2 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. 1 2 3 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. S2CID 36659104.
  7. 1 2 3 4 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. S2CID 16419929.
  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. S2CID 11164838.
  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.
  11. ↑ Sluder AE, Maina CV (April 2001). "Nuclear receptors in nematodes: themes and variations". Trends in Genetics. 17 (4): 206–13. doi:10.1016/S0168-9525(01)02242-9. PMID 11275326.
  12. ↑ Cheatle Jarvela AM, Pick L (2017). "The Function and Evolution of Nuclear Receptors in Insect Embryonic Development". Current Topics in Developmental Biology. 125: 39–70. doi:10.1016/bs.ctdb.2017.01.003. ISBN 9780128021729. PMID 28527580.
  13. ↑ Schaaf MJ (2017). "Nuclear receptor research in zebrafish". Journal of Molecular Endocrinology. 59 (1): R65–R76. doi:10.1530/JME-17-0031. PMID 28438785.
  14. 1 2 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): 580–90. doi:10.1101/gr.2160004. PMC 383302. PMID 15059999.
  15. ↑ Overington JP, Al-Lazikani B, Hopkins AL (December 2006). "How many drug targets are there?". Nature Reviews. Drug Discovery. 5 (12): 993–6. doi:10.1038/nrd2199. PMID 17139284. S2CID 11979420.
  16. ↑ Benoit G, Cooney A, Giguere V, Ingraham H, Lazar M, Muscat G, Perlmann T, Renaud JP, Schwabe J, Sladek F, Tsai MJ, Laudet V (December 2006). "International Union of Pharmacology. LXVI. Orphan nuclear receptors". Pharmacological Reviews. 58 (4): 798–836. doi:10.1124/pr.58.4.10. PMID 17132856. S2CID 2619263.
  17. ↑ Mohan R, Heyman RA (2003). "Orphan nuclear receptor modulators". Current Topics in Medicinal Chemistry. 3 (14): 1637–47. doi:10.2174/1568026033451709. PMID 14683519.
  18. ↑ Kumar R, Thompson EB (May 1999). "The structure of the nuclear hormone receptors". Steroids. 64 (5): 310–9. doi:10.1016/S0039-128X(99)00014-8. PMID 10406480. S2CID 18333397.
  19. ↑ Klinge CM (May 2000). "Estrogen receptor interaction with co-activators and co-repressors". Steroids. 65 (5): 227–51. doi:10.1016/S0039-128X(99)00107-5. PMID 10751636. S2CID 41160722.
  20. 1 2 Wärnmark A, Treuter E, Wright AP, Gustafsson JA (October 2003). "Activation functions 1 and 2 of nuclear receptors: molecular strategies for transcriptional activation". Molecular Endocrinology. 17 (10): 1901–9. doi:10.1210/me.2002-0384. PMID 12893880.
  21. ↑ Wu W, LoVerde PT (2021). "Identification and evolution of nuclear receptors in Platyhelminths". PLOS ONE. 16(8): e0250750 (8): e0250750. Bibcode:2021PLoSO..1650750W. doi:10.1371/journal.pone.0250750. PMC 8363021. PMID 34388160.
  22. ↑ Weatherman RV, Fletterick RJ, Scanlan TS (1999). "Nuclear-receptor ligands and ligand-binding domains". Annual Review of Biochemistry. 68: 559–81. doi:10.1146/annurev.biochem.68.1.559. PMID 10872460.
  23. ↑ Chandra V, Huang P, Potluri N, Wu D, Kim Y, Rastinejad F (March 2013). "Multidomain integration in the structure of the HNF-4α nuclear receptor complex". Nature. 495 (7441): 394–8. Bibcode:2013Natur.495..394C. doi:10.1038/nature11966. PMC 3606643. PMID 23485969.
  24. ↑ Lou X, Toresson G, Benod C, Suh JH, Philips KJ, Webb P, Gustafsson JA (March 2014). "Structure of the retinoid X receptor α-liver X receptor β (RXRα-LXRβ) heterodimer on DNA". Nature Structural & Molecular Biology. 21 (3): 277–81. doi:10.1038/nsmb.2778. PMID 24561505. S2CID 23226682.
  25. ↑ PDB: 2C7A​; Roemer SC, Donham DC, Sherman L, Pon VH, Edwards DP, Churchill ME (December 2006). "Structure of the progesterone receptor-deoxyribonucleic acid complex: novel interactions required for binding to half-site response elements". Molecular Endocrinology. 20 (12): 3042–52. doi:10.1210/me.2005-0511. PMC 2532839. PMID 16931575.
  26. ↑ PDB: 3L0L​; Jin L, Martynowski D, Zheng S, Wada T, Xie W, Li Y (May 2010). "Structural basis for hydroxycholesterols as natural ligands of orphan nuclear receptor RORgamma". Molecular Endocrinology. 24 (5): 923–9. doi:10.1210/me.2009-0507. PMC 2870936. PMID 20203100.
  27. 1 2 3 4 Amoutzias GD, Pichler EE, Mian N, De Graaf D, Imsiridou A, Robinson-Rechavi M, Bornberg-Bauer E, Robertson DL, Oliver SG (July 2007). "A protein interaction atlas for the nuclear receptors: properties and quality of a hub-based dimerisation network". BMC Systems Biology. 1: 34. doi:10.1186/1752-0509-1-34. PMC 1971058. PMID 17672894.
  28. ↑ Linja MJ, Porkka KP, Kang Z, Savinainen KJ, Jänne OA, Tammela TL, Vessella RL, Palvimo JJ, Visakorpi T (February 2004). "Expression of androgen receptor coregulators in prostate cancer". Clinical Cancer Research. 10 (3): 1032–40. doi:10.1158/1078-0432.CCR-0990-3. PMID 14871982. S2CID 8038717.
  29. ↑ Klinge CM, Bodenner DL, Desai D, Niles RM, Traish AM (May 1997). "Binding of type II nuclear receptors and estrogen receptor to full and half-site estrogen response elements in vitro". Nucleic Acids Research. 25 (10): 1903–12. doi:10.1093/nar/25.10.1903. PMC 146682. PMID 9115356.
  30. ↑ Rual, Jean-François; Venkatesan, Kavitha; Hao, Tong; Hirozane-Kishikawa, Tomoko; Dricot, Amélie; Li, Ning; Berriz, Gabriel F.; Gibbons, Francis D.; Dreze, Matija; Ayivi-Guedehoussou, Nono; Klitgord, Niels (2005-10-20). "Towards a proteome-scale map of the human protein-protein interaction network". Nature. 437 (7062): 1173–1178. Bibcode:2005Natur.437.1173R. doi:10.1038/nature04209. ISSN 1476-4687. PMID 16189514. S2CID 4427026.
  31. ↑ Albers, Michael; Kranz, Harald; Kober, Ingo; Kaiser, Carmen; Klink, Martin; Suckow, Jörg; Kern, Rainer; Koegl, Manfred (February 2005). "Automated yeast two-hybrid screening for nuclear receptor-interacting proteins". Molecular & Cellular Proteomics. 4 (2): 205–213. doi:10.1074/mcp.M400169-MCP200. ISSN 1535-9476. PMID 15604093. S2CID 14876486.
  32. ↑ Glass CK, Rosenfeld MG (January 2000). "The coregulator exchange in transcriptional functions of nuclear receptors". Genes & Development. 14 (2): 121–41. doi:10.1101/gad.14.2.121. PMID 10652267. S2CID 12793980.
  33. ↑ Aranda A, Pascual A (July 2001). "Nuclear hormone receptors and gene expression". Physiological Reviews. 81 (3): 1269–304. doi:10.1152/physrev.2001.81.3.1269. hdl:10261/79944. PMID 11427696. S2CID 5972234.
  34. ↑ Copland JA, Sheffield-Moore M, Koldzic-Zivanovic N, Gentry S, Lamprou G, Tzortzatou-Stathopoulou F, Zoumpourlis V, Urban RJ, Vlahopoulos SA (June 2009). "Sex steroid receptors in skeletal differentiation and epithelial neoplasia: is tissue-specific intervention possible?". BioEssays. 31 (6): 629–41. doi:10.1002/bies.200800138. PMID 19382224. S2CID 205469320.
  35. ↑ Brzozowski AM, Pike AC, Dauter Z, Hubbard RE, Bonn T, Engström O, Ohman L, Greene GL, Gustafsson JA, Carlquist M (October 1997). "Molecular basis of agonism and antagonism in the oestrogen receptor". Nature. 389 (6652): 753–8. Bibcode:1997Natur.389..753B. doi:10.1038/39645. PMID 9338790. S2CID 4430999.
  36. ↑ Shiau AK, Barstad D, Loria PM, Cheng L, Kushner PJ, Agard DA, Greene GL (December 1998). "The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen". Cell. 95 (7): 927–37. doi:10.1016/S0092-8674(00)81717-1. PMID 9875847. S2CID 10265320.
  37. ↑ Gronemeyer H, Gustafsson JA, Laudet V (November 2004). "Principles for modulation of the nuclear receptor superfamily". Nature Reviews. Drug Discovery. 3 (11): 950–64. doi:10.1038/nrd1551. PMID 15520817. S2CID 205475111.
  38. ↑ Busch BB, Stevens WC, Martin R, Ordentlich P, Zhou S, Sapp DW, Horlick RA, Mohan R (November 2004). "Identification of a selective inverse agonist for the orphan nuclear receptor estrogen-related receptor alpha". Journal of Medicinal Chemistry. 47 (23): 5593–6. doi:10.1021/jm049334f. PMID 15509154.
  39. ↑ Smith CL, O'Malley BW (February 2004). "Coregulator function: a key to understanding tissue specificity of selective receptor modulators". Endocrine Reviews. 25 (1): 45–71. doi:10.1210/er.2003-0023. PMID 14769827.
  40. ↑ Pascual G, Glass CK (October 2006). "Nuclear receptors versus inflammation: mechanisms of transrepression". Trends in Endocrinology and Metabolism. 17 (8): 321–7. doi:10.1016/j.tem.2006.08.005. PMID 16942889. S2CID 19612552.
  41. ↑ Björnström L, Sjöberg M (June 2004). "Estrogen receptor-dependent activation of AP-1 via non-genomic signalling". Nuclear Receptor. 2 (1): 3. doi:10.1186/1478-1336-2-3. PMC 434532. PMID 15196329.
  42. ↑ 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 Research. 7 (1): R101–12. doi:10.1186/bcr958. PMC 1064104. PMID 15642158.
  43. ↑ Kousteni S, Bellido T, Plotkin LI, O'Brien CA, Bodenner DL, Han L, Han K, DiGregorio GB, Katzenellenbogen JA, Katzenellenbogen BS, Roberson PK, Weinstein RS, Jilka RL, Manolagas SC (March 2001). "Nongenotropic, sex-nonspecific signaling through the estrogen or androgen receptors: dissociation from transcriptional activity". Cell. 104 (5): 719–30. doi:10.1016/S0092-8674(01)00268-9. PMID 11257226. S2CID 10642274.
  44. ↑ Storey NM, Gentile S, Ullah H, Russo A, Muessel M, Erxleben C, Armstrong DL (March 2006). "Rapid signaling at the plasma membrane by a nuclear receptor for thyroid hormone". Proceedings of the National Academy of Sciences of the United States of America. 103 (13): 5197–201. Bibcode:2006PNAS..103.5197S. doi:10.1073/pnas.0600089103. PMC 1458817. PMID 16549781.
  45. ↑ Storey NM, O'Bryan JP, Armstrong DL (January 2002). "Rac and Rho mediate opposing hormonal regulation of the ether-a-go-go-related potassium channel". Current Biology. 12 (1): 27–33. doi:10.1016/S0960-9822(01)00625-X. PMID 11790300. S2CID 8608805.
  46. 1 2 Martin NP, Marron Fernandez de Velasco E, Mizuno F, Scappini EL, Gloss B, Erxleben C, Williams JG, Stapleton HM, Gentile S, Armstrong DL (September 2014). "A rapid cytoplasmic mechanism for PI3 kinase regulation by the nuclear thyroid hormone receptor, TRβ, and genetic evidence for its role in the maturation of mouse hippocampal synapses in vivo". Endocrinology. 155 (9): 3713–24. doi:10.1210/en.2013-2058. PMC 4138568. PMID 24932806.
  47. ↑ Gilbert ME (January 2004). "Alterations in synaptic transmission and plasticity in area CA1 of adult hippocampus following developmental hypothyroidism". Brain Research. Developmental Brain Research. 148 (1): 11–8. doi:10.1016/j.devbrainres.2003.09.018. PMID 14757514.
  48. ↑ Moeller LC, Broecker-Preuss M (August 2011). "Transcriptional regulation by nonclassical action of thyroid hormone". Thyroid Research. 4 Suppl 1: S6. doi:10.1186/1756-6614-4-S1-S6. PMC 3155112. PMID 21835053.
  49. 1 2 3 4 5 6 7 8 9 10 11 Kaur S, Jobling S, Jones CS, Noble LR, Routledge EJ, Lockyer AE (7 April 2015). "The nuclear receptors of Biomphalaria glabrata and Lottia gigantea: implications for developing new model organisms". PLOS ONE. 10 (4): e0121259. Bibcode:2015PLoSO..1021259K. doi:10.1371/journal.pone.0121259. PMC 4388693. PMID 25849443.
  50. ↑ 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): 169–77. doi:10.1016/s0166-6851(01)00412-1. PMID 11814569.
  51. ↑ "sex-1 (gene)". WormBase : Nematode Information Resource.
  52. ↑ Otte K, Kranz H, Kober I, Thompson P, Hoefer M, Haubold B, Remmel B, Voss H, Kaiser C, Albers M, Cheruvallath Z, Jackson D, Casari G, Koegl M, Pääbo S, Mous J, Kremoser C, Deuschle U (February 2003). "Identification of farnesoid X receptor beta as a novel mammalian nuclear receptor sensing lanosterol". Molecular and Cellular Biology. 23 (3): 864–72. doi:10.1128/mcb.23.3.864-872.2003. PMC 140718. PMID 12529392.
  53. ↑ "FlyBase Gene Report: Dmel\Hr96". FlyBase. Retrieved 14 August 2019.
  54. 1 2 Schwabe JW, Teichmann SA (January 2004). "Nuclear receptors: the evolution of diversity". Science's STKE. 2004 (217): pe4. doi:10.1126/stke.2172004pe4. PMID 14747695. S2CID 20835274.
  55. ↑ Kruse SW, Suino-Powell K, Zhou XE, Kretschman JE, Reynolds R, Vonrhein C, et al. (September 2008). "Identification of COUP-TFII orphan nuclear receptor as a retinoic acid-activated receptor". PLOS Biology. 6 (9): e227. doi:10.1371/journal.pbio.0060227. PMC 2535662. PMID 18798693.
  56. ↑ Markov GV, Gutierrez-Mazariegos J, Pitrat D, Billas IM, Bonneton F, Moras D, et al. (March 2017). "Origin of an ancient hormone/receptor couple revealed by resurrection of an ancestral estrogen". Science Advances. 3 (3): e1601778. Bibcode:2017SciA....3E1778M. doi:10.1126/sciadv.1601778. PMC 5375646. PMID 28435861.
  57. 1 2 Khalturin K, Billas I, Chebaro Y, Reitzel AM, Tarrant AM, Laudet V, Markov GV (November 2018). "NR3E receptors in cnidarians : a new family of steroid receptor relatives extends the possible mechanisms for ligand binding". J Steroid Biochem Mol Biol. 184: 11–19. doi:10.1016/j.jsbmb.2018.06.014. PMC 6240368. PMID 29940311.
  58. ↑ Wu W, Niles EG, Hirai H, LoVerde PT (February 2007). "Evolution of a novel subfamily of nuclear receptors with members that each contain two DNA binding domains". BMC Evolutionary Biology. 7: 27. doi:10.1186/1471-2148-7-27. PMC 1810520. PMID 17319953.
  59. ↑ Huang W, Xu F, Li J, Li L, Que H, Zhang G (August 2015). "Evolution of a novel nuclear receptor subfamily with emphasis on the member from the Pacific oyster Crassostrea gigas". Gene. 567 (2): 164–72. doi:10.1016/j.gene.2015.04.082. PMID 25956376.
  60. ↑ "nhr-1 (gene)". WormBase : Nematode Information Resource.
  61. ↑ Marxreiter S, Thummel CS (February 2018). "Adult functions for the Drosophila DHR78 nuclear receptor". Developmental Dynamics. 247 (2): 315–322. doi:10.1002/dvdy.24608. PMC 5771960. PMID 29171103.
  62. ↑ 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.
  63. ↑ Moore DD (January 1990). "Diversity and unity in the nuclear hormone receptors: a terpenoid receptor superfamily". The New Biologist. 2 (1): 100–5. PMID 1964083.
  64. ↑ Laudet V, Hänni C, Coll J, Catzeflis F, Stéhelin D (March 1992). "Evolution of the nuclear receptor gene superfamily". The EMBO Journal. 11 (3): 1003–13. doi:10.1002/j.1460-2075.1992.tb05139.x. PMC 556541. PMID 1312460.
  65. ↑ Escriva H, Safi R, Hänni C, Langlois MC, Saumitou-Laprade P, Stehelin D, Capron A, Pierce R, Laudet V (June 1997). "Ligand binding was acquired during evolution of nuclear receptors". Proceedings of the National Academy of Sciences of the United States of America. 94 (13): 6803–8. Bibcode:1997PNAS...94.6803E. doi:10.1073/pnas.94.13.6803. PMC 21239. PMID 9192646.
  66. 1 2 3 Escriva H, Delaunay F, Laudet V (August 2000). "Ligand binding and nuclear receptor evolution". BioEssays. 22 (8): 717–27. doi:10.1002/1521-1878(200008)22:8<717::AID-BIES5>3.0.CO;2-I. PMID 10918302.
  67. ↑ 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.
  68. 1 2 Markov GV, Laudet V (March 2011). "Origin and evolution of the ligand-binding ability of nuclear receptors". Molecular and Cellular Endocrinology. Evolution of Nuclear Hormone Receptors. 334 (1–2): 21–30. doi:10.1016/j.mce.2010.10.017. PMID 21055443. S2CID 33537979.
  69. ↑ Thornton JW, Need E, Crews D (September 2003). "Resurrecting the ancestral steroid receptor: ancient origin of estrogen signaling". Science. 301 (5640): 1714–7. Bibcode:2003Sci...301.1714T. doi:10.1126/science.1086185. PMID 14500980. S2CID 37628350.
  70. ↑ Tata JR (June 2005). "One hundred years of hormones". EMBO Reports. 6 (6): 490–6. doi:10.1038/sj.embor.7400444. PMC 1369102. PMID 15940278.
This article is issued from Offline. The text is licensed under Creative Commons - Attribution - Sharealike. Additional terms may apply for the media files.