Misplaced Pages

#167832

61-397: 6256 20181 ENSG00000186350 ENSMUSG00000015846 P19793 P28700 NM_002957 NM_001291920 NM_001291921 NM_001290481 NM_001290482 NM_011305 NP_001278849 NP_001278850 NP_002948 NP_001277410 NP_001277411 NP_035435 Retinoid X receptor alpha ( RXR-alpha ), also known as NR2B1 (nuclear receptor subfamily 2, group B, member 1)

122-563: A conformational change activating the receptor. The result is up- or down-regulation of gene expression. A unique property of nuclear receptors that differentiates them from other classes of receptors is their direct control of genomic DNA. Nuclear receptors play key roles in both embryonic development and adult homeostasis. As discussed below, nuclear receptors are classified according to mechanism or homology . Nuclear receptors are specific to metazoans (animals) and are not found in protists , algae , fungi , or plants. Amongst

183-469: A binding affinity. In general, high-affinity ligand binding results from greater attractive forces between the ligand and its receptor while low-affinity ligand binding involves less attractive force. In general, high-affinity binding results in a higher occupancy of the receptor by its ligand than is the case for low-affinity binding; the residence time (lifetime of the receptor-ligand complex) does not correlate. High-affinity binding of ligands to receptors

244-495: 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

305-640: 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

366-440: 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". Knockout studies on mice and fruit flies support such a merged group. A topic of debate has been on the identity of the ancestral nuclear receptor as either a ligand-binding or an orphan receptor . This debate began more than twenty-five years ago when

427-408: A highly specific receptor for a particular molecule. Below is a brief selection of key events in the history of nuclear receptor research. Ligand (biochemistry) In biochemistry and pharmacology , a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. The etymology stems from Latin ligare , which means 'to bind'. In protein-ligand binding,

488-499: A hydrophobic protein (e.g. lipid-gated ion channels ) determining the affinity is complicated by non-specific hydrophobic interactions. Non-specific hydrophobic interactions can be overcome when the affinity of the ligand is high. For example, PIP2 binds with high affinity to PIP2 gated ion channels. Bivalent ligands consist of two drug-like molecules (pharmacophores or ligands) connected by an inert linker. There are various kinds of bivalent ligands and are often classified based on what

549-500: A ligand required to displace 50% of a fixed concentration of reference ligand is determined. The K i value can be estimated from IC 50 through the Cheng Prusoff equation . Ligand affinities can also be measured directly as a dissociation constant (K d ) using methods such as fluorescence quenching , isothermal titration calorimetry or surface plasmon resonance . Low-affinity binding (high K i level) implies that

610-497: 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. Most nuclear receptors have molecular masses between 50,000 and 100,000 daltons . Nuclear receptors are modular in structure and contain

671-481: A potential mechanism for integrating regulation of development and metabolism by thyroid hormone and receptor tyrosine kinases. In addition, thyroid hormone signaling through PI3K can alter gene expression. The following is a list of the 48 known human nuclear receptors (and their orthologs in other species) categorized according to sequence homology . The list also includes selected family members that lack human orthologs (NRNC symbol highlighted in yellow). Of

SECTION 10

#1732801125168

732-644: A process known as transrepression . One example of a nuclear receptor that are able to transrepress is the glucocorticoid receptor (GR). Furthermore, certain GR ligands known as Selective Glucocorticoid Receptor Agonists ( SEGRAs ) are able to activate GR in such a way that GR more strongly transrepresses than transactivates. This selectivity increases the separation between the desired antiinflammatory effects and undesired metabolic side effects of these selective glucocorticoids . The classical direct effects of nuclear receptors on gene regulation normally take hours before

793-423: A relatively high concentration of a ligand is required before the binding site is maximally occupied and the maximum physiological response to the ligand is achieved. In the example shown to the right, two different ligands bind to the same receptor binding site. Only one of the agonists shown can maximally stimulate the receptor and, thus, can be defined as a full agonist . An agonist that can only partially activate

854-407: A relatively low concentration of a ligand is adequate to maximally occupy a ligand-binding site and trigger a physiological response. Receptor affinity is measured by an inhibition constant or K i value, the concentration required to occupy 50% of the receptor. Ligand affinities are most often measured indirectly as an IC 50 value from a competition binding experiment where the concentration of

915-601: A single tyrosine to phenylalanine substitution in TRβ without disrupting direct gene regulation. When mice were created with this single, conservative amino acid substitution in TRβ, synaptic maturation and plasticity in the hippocampus was impaired almost as effectively as completely blocking thyroid hormone synthesis. This mechanism appears to be conserved in all mammals but not in TRα or any other nuclear receptors. Thus, phosphotyrosine-dependent association of TRβ with PI3K provides

976-494: 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 receptors, in contrast to type I, are retained in

1037-503: 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. 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. Nevertheless, there exists specificity, with members of

1098-504: A tagged ligand and an untagged ligand. Real-time based methods, which are often label-free, such as surface plasmon resonance , dual-polarization interferometry and multi-parametric surface plasmon resonance (MP-SPR) can not only quantify the affinity from concentration based assays; but also from the kinetics of association and dissociation, and in the later cases, the conformational change induced upon binding. MP-SPR also enables measurements in high saline dissociation buffers thanks to

1159-454: A unique optical setup. Microscale thermophoresis (MST), an immobilization-free method was developed. This method allows the determination of the binding affinity without any limitation to the ligand's molecular weight. For the use of statistical mechanics in a quantitative study of the ligand-receptor binding affinity, see the comprehensive article on the configurational partition function . Binding affinity data alone does not determine

1220-494: A variable length of DNA, and the second half-site has a sequence inverted from the first (inverted repeat). Type I nuclear receptors include members of subfamily 3, such as the androgen receptor , estrogen receptors , glucocorticoid receptor , and progesterone receptor . It has been noted that some of the NR subfamily 2 nuclear receptors may bind to direct repeat instead of inverted repeat HREs. In addition, some nuclear receptors that bind either as monomers or dimers, with only

1281-578: A variant of type I, and type IV that bind DNA as monomers have also been identified. Accordingly, nuclear receptors may be subdivided into the following four mechanistic classes: 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

SECTION 20

#1732801125168

1342-528: Is a nuclear receptor that in humans is encoded by the RXRA gene. Retinoid X receptors (RXRs) and retinoic acid receptors (RARs), are nuclear receptors that mediate the biological effects of retinoids by their involvement in retinoic acid -mediated gene activation. These receptors exert their action by binding, as homodimers or heterodimers, to specific sequences in the promoters of target genes and regulating their transcription. The protein encoded by this gene

1403-477: Is a function of charge, hydrophobicity , and molecular structure. Binding occurs by intermolecular forces , such as ionic bonds , hydrogen bonds and Van der Waals forces . The association or docking is actually reversible through dissociation . Measurably irreversible covalent bonding between a ligand and target molecule is atypical in biological systems. In contrast to the definition of ligand in metalorganic and inorganic chemistry , in biochemistry it

1464-455: Is a member of the steroid and thyroid hormone receptor superfamily of transcription factors . In the absence of ligand, the RXR-RAR heterodimers associate with a multiprotein complex containing transcription corepressors that induce histone deacetylation, chromatin condensation and transcriptional suppression. On ligand binding, the corepressors dissociate from the receptors and associate with

1525-522: Is ambiguous whether the ligand generally binds at a metal site, as is the case in hemoglobin . In general, the interpretation of ligand is contextual with regards to what sort of binding has been observed. Ligand binding to a receptor protein alters the conformation by affecting the three-dimensional shape orientation. The conformation of a receptor protein composes the functional state. Ligands include substrates , inhibitors , activators , signaling lipids , and neurotransmitters . The rate of binding

1586-680: Is called affinity , and this measurement typifies a tendency or strength of the effect. Binding affinity is actualized not only by host–guest interactions, but also by solvent effects that can play a dominant, steric role which drives non-covalent binding in solution. The solvent provides a chemical environment for the ligand and receptor to adapt, and thus accept or reject each other as partners. Radioligands are radioisotope labeled compounds used in vivo as tracers in PET studies and for in vitro binding studies. The interaction of ligands with their binding sites can be characterized in terms of

1647-428: 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

1708-405: Is often physiologically important when some of the binding energy can be used to cause a conformational change in the receptor, resulting in altered behavior for example of an associated ion channel or enzyme . A ligand that can bind to and alter the function of the receptor that triggers a physiological response is called a receptor agonist . Ligands that bind to a receptor but fail to activate

1769-503: The United States National Library of Medicine , which is in the public domain . Nuclear receptor In the field of molecular biology , nuclear receptors are a class of proteins responsible for sensing steroids , thyroid hormones , vitamins , and certain other molecules. These intracellular receptors work with other proteins to regulate the expression of specific genes , thereby controlling

1830-417: The development , homeostasis , and metabolism of the organism. Nuclear receptors bind directly to DNA regulating the expression of adjacent genes; hence these receptors are classified as transcription factors . The regulation of gene expression by nuclear receptors often occurs in the presence of a ligand —a molecule that affects the receptor's behavior. Ligand binding to a nuclear receptor results in

1891-596: 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 . Type III nuclear receptors (principally NR subfamily 2) are similar to type I receptors in that both classes bind to DNA as homodimers. However, type III nuclear receptors, in contrast to type I, bind to direct repeat instead of inverted repeat HREs. Type IV nuclear receptors bind either as monomers or dimers, but only

Retinoid X receptor alpha - Misplaced Pages Continue

1952-619: The absence of ligand. Small lipophilic substances such as natural hormones diffuse through the cell membrane and bind to nuclear receptors located in the cytosol (type I NR) or nucleus (type II NR) of the cell. Binding causes a conformational change in the receptor which, depending on the class of receptor, triggers a cascade of downstream events that direct the NRs to DNA transcription regulation sites which result in up or down-regulation of gene expression. They generally function as homo/heterodimers. In addition, two additional classes, type III which are

2013-756: The activity of the endogenous hormones cortisol and progesterone respectively. Antagonist ligands work by inducing a conformation of the receptor which prevents coactivator binding, and promotes corepressor binding (see lower half of the figure to the right). 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 . 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

2074-466: The association of histones to DNA, and therefore represses gene transcription. Depending on the receptor involved, the chemical structure of the ligand and the tissue that is being affected, nuclear receptor ligands may display dramatically diverse effects ranging in a spectrum from agonism to antagonism to inverse agonism. The activity of endogenous ligands (such as the hormones estradiol and testosterone ) when bound to their cognate nuclear receptors

2135-404: 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,

2196-405: The coactivators leading to transcriptional activation. The RXRA/PPARA heterodimer is required for PPARA transcriptional activity on fatty acid oxidation genes such as ACOX1 and the cytochrome P450 system genes. Click on genes, proteins and metabolites below to link to respective articles. Retinoid X receptor alpha has been shown to interact with: This article incorporates text from

2257-403: The cytosol or nucleus. Furthermore, these membrane associated receptors function through alternative signal transduction mechanisms not involving gene regulation. While it has been hypothesized that there are several membrane associated receptors for nuclear hormones, many of the rapid effects have been shown to require canonical nuclear receptors. However, testing the relative importance of

2318-439: 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

2379-694: The early-branching animal lineages with sequenced genomes, two have been reported from the sponge Amphimedon queenslandica , two from the comb jelly Mnemiopsis leidyi four from the placozoan Trichoplax adhaerens and 17 from the cnidarian Nematostella vectensis . There are 270 nuclear receptors in the roundworm Caenorhabditis elegans alone, 21 in the fruit fly and other insects, 73 in zebrafish . Humans, mice, and rats have respectively 48, 49, and 47 nuclear receptors each. Ligands that bind to and activate nuclear receptors include lipophilic substances such as endogenous hormones , vitamins A and D , and xenobiotic hormones . Because

2440-483: 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

2501-1159: The evolution, function, allostery and folding of protein compexes. A privileged scaffold is a molecular framework or chemical moiety that is statistically recurrent among known drugs or among a specific array of biologically active compounds. These privileged elements can be used as a basis for designing new active biological compounds or compound libraries. Main methods to study protein–ligand interactions are principal hydrodynamic and calorimetric techniques, and principal spectroscopic and structural methods such as Other techniques include: fluorescence intensity, bimolecular fluorescence complementation, FRET (fluorescent resonance energy transfer) / FRET quenching surface plasmon resonance, bio-layer interferometry , Coimmunopreciptation indirect ELISA, equilibrium dialysis, gel electrophoresis, far western blot, fluorescence polarization anisotropy, electron paramagnetic resonance, microscale thermophoresis , switchSENSE . The dramatically increased computing power of supercomputers and personal computers has made it possible to study protein–ligand interactions also by means of computational chemistry . For example,

Retinoid X receptor alpha - Misplaced Pages Continue

2562-575: The expression of a large number of genes is regulated by nuclear receptors, ligands that activate these receptors can have profound effects on the organism. Many of these regulated genes are associated with various diseases, which explains why the molecular targets of approximately 13% of U.S. Food and Drug Administration (FDA) approved drugs target nuclear receptors. A number of nuclear receptors, referred to as orphan receptors , have no known (or at least generally agreed upon) endogenous ligands. Some of these receptors such as FXR , LXR , and PPAR bind

2623-469: 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

2684-523: The first ligands were identified as mammalian steroid and thyroid hormones. Shortly thereafter, the identification of the ecdysone receptor in Drosophila introduced the idea that nuclear receptors were hormonal receptors that bind ligands with a nanomolar affinity. At the time, the three known nuclear receptor ligands were steroids, retinoids, and thyroid hormone, and of those three, both steroids and retinoids were products of terpenoid metabolism. Thus, it

2745-755: The following domains : The DNA-binding (C), and ligand binding (E) domains are independently well folded and structurally stable while the N-terminal (A/B), hinge region (D) and optional C-terminal (F) domains may be conformationally flexible and disordered. Domains relative orientations are very different by comparing three known multi-domain crystal structures, two of them binding on DR1 (DBDs separated by 1 bp), one binding on DR4 (by 4 bp). 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

2806-435: 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 ). This signaling can be blocked by

2867-433: The ligand behaves as an antagonist. The most common mechanism of nuclear receptor action involves direct binding of the nuclear receptor to a DNA hormone response element. This mechanism is referred to as transactivation . However some nuclear receptors not only have the ability to directly bind to DNA, but also to other transcription factors. This binding often results in deactivation of the second transcription factor in

2928-448: The ligand is usually a molecule which produces a signal by binding to a site on a target protein . The binding typically results in a change of conformational isomerism (conformation) of the target protein. In DNA-ligand binding studies, the ligand can be a small molecule, ion , or protein which binds to the DNA double helix . The relationship between ligand and binding partner

2989-406: The nucleus regardless of the ligand binding status and in addition bind as hetero-dimers (usually with RXR ) to DNA. In the absence of ligand, type II nuclear receptors are often complexed with corepressor proteins. Ligand binding to the nuclear receptor causes dissociation of corepressor and recruitment of coactivator proteins. Additional proteins including RNA polymerase are then recruited to

3050-417: The number of protein chains they bind. "Monodesmic" ligands (μόνος: single, δεσμός: binding) are ligands that bind a single protein chain, while "polydesmic" ligands (πολοί: many) are frequent in protein complexes, and are ligands that bind more than one protein chain, typically in or near protein interfaces. Recent research shows that the type of ligands and binding site structure has profound consequences for

3111-1124: The opioid receptor system. Bivalent ligands were also reported early on by Micheal Conn and coworkers for the gonadotropin-releasing hormone receptor . Since these early reports, there have been many bivalent ligands reported for various G protein-coupled receptor (GPCR) systems including cannabinoid, serotonin, oxytocin, and melanocortin receptor systems, and for GPCR - LIC systems ( D2 and nACh receptors ). Bivalent ligands usually tend to be larger than their monovalent counterparts, and therefore, not 'drug-like' as in Lipinski's rule of five . Many believe this limits their applicability in clinical settings. In spite of these beliefs, there have been many ligands that have reported successful pre-clinical animal studies. Given that some bivalent ligands can have many advantages compared to their monovalent counterparts (such as tissue selectivity, increased binding affinity, and increased potency or efficacy), bivalents may offer some clinical advantages as well. Ligands of proteins can be characterized also by

SECTION 50

#1732801125168

3172-442: The overall potency of a drug or a naturally produced (biosynthesized) hormone. Potency is a result of the complex interplay of both the binding affinity and the ligand efficacy. Ligand efficacy refers to the ability of the ligand to produce a biological response upon binding to the target receptor and the quantitative magnitude of this response. This response may be as an agonist , antagonist , or inverse agonist , depending on

3233-462: The pharmacophores target. Homobivalent ligands target two of the same receptor types. Heterobivalent ligands target two different receptor types. Bitopic ligands target an orthosteric binding sites and allosteric binding sites on the same receptor. In scientific research, bivalent ligands have been used to study receptor dimers and to investigate their properties. This class of ligands was pioneered by Philip S. Portoghese and coworkers while studying

3294-444: The physiological response are receptor antagonists . Agonist binding to a receptor can be characterized both in terms of how much physiological response can be triggered (that is, the efficacy ) and in terms of the concentration of the agonist that is required to produce the physiological response (often measured as EC 50 , the concentration required to produce the half-maximal response). High-affinity ligand binding implies that

3355-401: The physiological response is called a partial agonist . In this example, the concentration at which the full agonist (red curve) can half-maximally activate the receptor is about 5 x 10 Molar (nM = nanomolar ). Binding affinity is most commonly determined using a radiolabeled ligand, known as a tagged ligand. Homologous competitive binding experiments involve binding competition between

3416-457: The physiological response produced. Selective ligands have a tendency to bind to very limited kinds of receptor, whereas non-selective ligands bind to several types of receptors. This plays an important role in pharmacology , where drugs that are non-selective tend to have more adverse effects , because they bind to several other receptors in addition to the one generating the desired effect. For hydrophobic ligands (e.g. PIP2) in complex with

3477-525: 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). Nuclear receptors bound to hormone response elements recruit a significant number of other proteins (referred to as transcription coregulators ) that facilitate or inhibit the transcription of the associated target gene into mRNA. The function of these coregulators are varied and include chromatin remodeling (making

3538-403: The target gene either more or less accessible to transcription) or a bridging function to stabilize the binding of other coregulatory proteins. Nuclear receptors may bind specifically to a number of coregulator proteins, and thereby influence cellular mechanisms of signal transduction both directly, as well as indirectly. Binding of agonist ligands (see section below) to nuclear receptors induces

3599-434: The two 0-families, 0A has a family 1-like DBD, and 0B has a unique LBD. The second DBD of family 7 is probably related to the family 1 DBD. Three probably family-1 NRs from Biomphalaria glabrata possess a DBD along with a family 0B-like LBD. The placement of C. elegans nhr-1 ( Q21878 ) is disputed: although most sources place it as NR1K1, manual annotation at WormBase considers it a member of NR2A. There used to be

3660-502: Was postulated that ancestral receptor would have been liganded by a terpenoid molecule. In 1992, a comparison of the DNA-binding domain of all known nuclear receptors led to the construction of a phylogenic tree of nuclear receptor that indicated that all nuclear receptors shared a common ancestor. As a result, there was an increased effort upon uncovering the state of the first nuclear receptor, and by 1997 an alternative hypothesis

3721-446: Was suggested: the ancestral nuclear receptor was an orphan receptor and it acquired ligand-binding ability over time This hypothesis was proposed based on the following arguments: Over the next 10 years, experiments were conducted to test this hypothesis and counterarguments soon emerged: 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

SECTION 60

#1732801125168
#167832