In the field of molecular biology, nuclear receptors are a class of proteins found within the interior of cells that are responsible for sensing the presence of hormones and certain other molecules. In response, these nuclear receptors affected by the hormones work in concert with other proteins to regulate the expression of specific genes, thereby regulating the mechanisms of the body (metabolism, developmental characteristics, homeostatic functions)
Nuclear receptors have the ability to directly bind to DNA and regulate the expression of adjacent genes, hence these receptors are classified as transcription factors. The regulation of gene expression by nuclear receptors only happens when a ligand—a molecule which affects the receptor's behavior—is present. More specifically, ligand binding to a nuclear receptor results in a conformational change in the receptor which in turn activates the receptor resulting in up-regulation of gene expression.
A unique property of nuclear receptors which differentiate them from other classes of receptors is their ability to directly interact with and control the expression of genomic DNA. Consequently nuclear receptors play key roles in development and homeostasis of organisms. As discussed in more detail below, nuclear receptors may be classified either according to mechanism or homology.
Ligands that bind to and activate nuclear receptors include lipophilic substances such as endogenous hormones, vitamins A and D, and xenobiotic endocrine disruptors. Because the expression of a large number of genes is regulated by nuclear receptors, ligands that activate these receptors can have profound effects on the organism. Many of these regulated genes are associated with various diseases which explains why the molecular targets of approximately 13% of FDA approved drugs are nuclear receptors.
A number of nuclear receptors, referred to as orphan receptors, have no known (or at least generally agreed upon) endogenous ligands. Some of these receptors such as FXR, LXR, and PPAR bind a number of metabolic intermediates such as fatty acids, bile acids and/or sterols with relatively low affinity. These receptors hence may function as metabolic sensors. Other nuclear receptors, such as CAR and PXR appear to function as xenobiotic sensors up-regulating the expression of cytochrome P450 enzymes that metabolize these xenobiotics.
Nuclear receptors are modular in structure and contain the following domains:
- A-B) N-terminal regulatory domain: Contains the activation function 1 (AF-1) whose action is independent of the presence of ligand. The transcriptional activation of AF-1 is normally very weak, but it does synergize with AF-2 (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) (IPR001628): Highly conserved domain containing two zinc fingers (SCOP 57715) which binds to specific sequences of DNA called hormone response elements (HRE).
- D) Hinge region: Thought to be a flexible domain which connects the DBD with the LBD. Influences intracellular trafficking and subcellular distribution.
- E) Ligand binding domain (LBD) (IPR000536): 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 (SCOP 48507) in which three anti parallel alpha helices (the "sandwich filling") are flanked by two alpha helices on one side and three on the other (the "bread"). The ligand binding cavity is within the interior of the LBD and just below three anti parallel alpha helical sandwich "filling". Along with the DBD, the LBD contributes to the dimerization interface of the receptor and in addition, binds coactivator and corepressor proteins. Contains the activation function 2 (AF-2) whose action is dependent on the presence of bound ligand.
- F) C-terminal domain: Variable in sequence between various nuclear receptors.
Mechanism of action
Nuclear receptors (NRs) may be classified into two broad classes according to their mechanism of action and subcellular distribution in the absence of ligand.
Small lipophilic substances such as natural hormones diffuse past the cell membrane and bind to nuclear receptors located in the cytosol (type I NR) or nucleus (type II NR) of the cell. This causes a change in the conformation of the receptor which depending on the mechanistic class (type I or II), triggers a number of down stream events that eventually results in up or down regulation of gene expression.
Accordingly, nuclear receptors may be subdivided into the following two mechanistic classes:
Ligand binding to type I nuclear receptors in the cytosol (includes members of the NR subfamily 3) results in the dissociation of heat shock proteins, homo-dimerization, translocation (i.e., active transport) from the cytoplasm into the cell nucleus, and binding to specific sequences of DNA known as hormone response elements (HRE's). Type I nuclear receptors bind to HREs consisting of two half sites separated by a variable length of DNA and the second half site has a sequence inverted from the first (inverted repeat).
The nuclear receptor/DNA complex then recruits other proteins which transcribe DNA downstream from the HRE into messenger RNA and eventually protein which causes a change in cell function.
Type II receptors (principally NR subfamily 1) in contrast are retained in the nucleus regardless of the ligand binding status and in addition bind as hetero-dimers (usually with RXR) to DNA. In the absence of ligand, type II nuclear receptors are often complexed with corepressor proteins. Ligand binding to the nuclear receptor causes dissociation of corepressor and recruitment of coactivator proteins. Additional proteins including RNA polymerase are then recruited to the NR/DNA complex which translate DNA into messenger RNA.
Type III nuclear receptors (principally NR subfamily 2) are similar to type I receptors in that both classes bind to DNA has homodimers. However type III in contrast type I nuclear receptors bind to direct repeat instead of inverted repeat HREs.
Type IV nuclear receptors bind either as monomers or dimers, but only a single DNA binding domain of the receptor binds to a single half site HRE. Examples of type IV receptors are found in most of the NR subfamilies.
Nuclear receptors bound to hormone response elements recruit a significant number of other proteins (referred to as transcription coregulators) which facilitate or inhibit the transcription of the associated target gene into mRNA. The function of these coregulators are varied and include chromatin remodeling (making the target gene either more or less accessible to transcription) or a bridging function to stabilize the binding of other coregulatory proteins.
Binding of agonist ligands (see section below) to nuclear receptors induces a conformation of the receptor that preferentially binds coactivator proteins. These proteins often have an intrinsic histone acetyltransferase (HAT) activity which weakens the association of histones to DNA, and therefore promotes gene transcription.
Binding of antagonist ligands to nuclear receptors in contrast induces a conformation of the receptor that preferentially binds corepressor proteins. These proteins in turn recruit histone deacetylases (HDACs) which strengthens the association of histones to DNA, and therefore represses gene transcription.
Agonism vs Antagonism
Depending on the receptor involved, the chemical structure of the ligand and the tissue that is being affected, nuclear receptor ligands may display dramatically diverse effects ranging in a spectrum from agonism to antagonism to inverse agonism.
The activity of endogenous ligands (such as the hormones estradiol and testosterone) when bound to their cognate nuclear receptors is normally to upregulate gene expression. This stimulation of gene expression by the ligand is referred to as an agonist response. The agonistic effects of endogenous hormones can also be mimicked by certain synthetic ligands, for example, the glucocorticoid receptor antiiflammatory drug dexamethasone. Agonist ligands work by inducing a conformation of the receptor which favors coactivator binding (see upper half of the figure to the right).
Other synthetic nuclear receptor ligands have no apparent effect on gene transcription in the absence of endogenous ligand. However they block the effect of agonist through competitive binding to the same binding site in the nuclear receptor. These ligands are referred to as antagonists. An example of antagonistic nuclear receptor drug is mifepristone which binds to the glucocorticoid and progesterone receptors and therefore block the activity of the endogenous hormones cortisol and progesterone respectively. Antagonist ligands work by inducing a conformation of the receptor which prevents coactivator and promotes corepressor binding (see lower half of the figure to the right).
Finally, some nuclear receptors promote a low level of gene transcription in the absence of agonists (also referred to as basal or constitutive activity). Synthetic ligands which reduce this basal level of activity in nuclear receptors are known as inverse agonists.
Selective receptor modulators
A number of drugs that work through nuclear receptors display an agonist response in some tissue while an antagonistic response in other tissues. This behavior may have substantial benefits since it may allow retaining the desired beneficial therapeutic effects of a drug while minimizing undesirable side effects. Drugs with this mixed agonist/antagonist profile of action are referred to as selective receptor modulators (SRMs). Examples include Selective Estrogen Receptor Modulators (SERMs) and Selective Progesterone Receptor Modulators (SPRMs). The mechanism of action of SRMs may vary depending on the chemical structure of the ligand and the receptor involved, however it is thought that many SRMs work by promoting a conformation of the receptor that is closely balanced between agonism and antagonism. In tissues where the concentration of coactivator proteins is higher than corepressors, the equilibrium is shifted in the agonist direction. Conversely in tissues where corepressors dominate, the ligand behaves as an antagonist.
The most common mechanism of nuclear receptor action involves direct binding of the nuclear receptor to a DNA hormone response element. This mechanism is referred to as transactivation. However some nuclear receptors not only have the ability to directly bind to DNA, but also to other transcription factors. This binding often results in deactivation of the second transcription factor in a process known as transrepresson.
The classical direct effects of nuclear receptors on gene regulation normally takes hours before a functional effect is seen in cells because of the large number of intermediate steps between nuclear receptor activation and changes in protein expression levels. However it has been observed that some effects from the application of hormones such as estrogen occur within minutes which is inconsistent with the classical mechanism nuclear receptor action. While the molecular target for these non-genomic effects of nuclear receptors has not been conclusively demonstrated, it has been hypothesized that there are variants of nuclear receptors which are membrane associated instead of being localized in the cytosol or nucleus. Furthermore these membrane associated receptors function through alternative signal transduction mechanisms not involving gene regulation.
The following is a list of the 48 known human nuclear receptors categorized according to sequence homology. The list is organized as follows:
- Group: name (endogenous ligand if common to entire group)
- Member: name (abbreviation; NRNC Symbol, gene) (endogenous ligand)
Subfamily 1: Thyroid Hormone Receptor-like
- Group A: Thyroid hormone receptor (Thyroid hormone)
- 1: Thyroid hormone receptor-α (TRα; NR1A1, THRA)
- 2: Thyroid hormone receptor-β (TRβ; NR1A2, THRB)
- Group B: Retinoic acid receptor (Vitamin A and related compounds)
- 1: Retinoic acid receptor-α (RARα; NR1B1, RARA)
- 2: Retinoic acid receptor-β (RARβ; NR1B2, RARB)
- 3: Retinoic acid receptor-γ (RARγ; NR1B3, RARG)
- Group C: Peroxisome proliferator-activated receptor
- 1: Peroxisome proliferator-activated receptor-α (PPARα; NR1C1, PPARA)
- 2: Peroxisome proliferator-activated receptor-β/δ (PPARβ/δ; NR1C2, PPARD)
- 3: Peroxisome proliferator-activated receptor-γ (PPARγ; NR1C3, PPARG)
- Group D: Rev-ErbA
- 1: Rev-ErbAα (Rev-ErbAα; NR1D1)
- 2: Rev-ErbAβ (Rev-ErbAβ; NR1D2)
- Group F: RAR-related orphan receptor
- 1: RAR-related orphan receptor-α (RORα; NR1F1, RORA)
- 2: RAR-related orphan receptor-β (RORβ; NR1F2, RORB)
- 3: RAR-related orphan receptor-γ (RORγ; NR1F3, RORC)
- Group H: Liver X receptor-like
- 3: Liver X receptor-α (LXRα; NR1H3)
- 2: Liver X receptor-β (LXRβ; NR1H2)
- 4: Farnesoid X receptor (FXR; NR1H4)
- Group I: Vitamin D receptor-like
- 1: Vitamin D receptor (VDR; NR1I1, VDR) (vitamin D)
- 2: Pregnane X receptor (PXR; NR1I2)
- 3: Constitutive androstane receptor (CAR; NR1I3)
Subfamily 2: Retinoid X Receptor-like
- Group A: Hepatocyte nuclear factor-4 (HNF4)
- 1: Hepatocyte nuclear factor-4-α (HNF4α; NR2A1, HNF4A)
- 2: Hepatocyte nuclear factor-4-γ (HNF4γ; NR2A2, HNF4G)
- Group B: Retinoid X receptor (RXRα)
- 1: Retinoid X receptor-α (RXRα; NR2B1, RXRA)
- 2: Retinoid X receptor-β (RXRβ; NR2B2, RXRB)
- 3: Retinoid X receptor-γ (RXRγ; NR2B3, RXRG)
- Group C: Testicular receptor
- 1: Testicular receptor 2 (TR2; NR2C1)
- 2: Testicular receptor 4 (TR4; NR2C2)
- Group E: TLX/PNR
- 1: Human homologue of the Drosophila tailless gene (TLX; NR2E1)
- 3: Photoreceptor cell-specific nuclear receptor (PNR; NR2E3)
- Group F: COUP/EAR
- 1: Chicken ovalbumin upstream promoter-transcription factor I (COUP-TFI; NR2F1)
- 2: Chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII; NR2F2)
- 6: V-erbA-related gene|V-erbA-related (EAR-2; NR2F6)
Subfamily 3: Estrogen Receptor-like
See also steroid and sex hormone receptors
- Group A: Estrogen receptor (Sex hormones: Estrogen)
- 1: Estrogen receptor-α (ERα; NR3A1, ESR1)
- 2: Estrogen receptor-β (ERβ; NR3A2, ESR2)
- Group B: Estrogen related receptor
- 1: Estrogen-related receptor-α (ERRα; NR3B1, ESRRA)
- 2: Estrogen-related receptor-β (ERRβ; NR3B2, ESRRB)
- 3: Estrogen-related receptor-γ (ERRγ; NR3B3, ESRRG)
- Group C: 3-Ketosteroid receptors
- 1: Glucocorticoid receptor (GR; NR3C1) (Cortisol)
- 2: Mineralocorticoid receptor (MR; NR3C2) (Aldosterone)
- 3: Progesterone receptor (PR; NR3C3, PGR) (Sex hormones: Progesterone)
- 4: Androgen receptor (AR; NR3C4, AR) (Sex hormones: Testosterone)
Subfamily 4: Nerve Growth Factor IB-like
- Group A: NGFIB/NURR1/NOR1
- 1: Nerve Growth factor IB (NGFIB; NR4A1)
- 2: Nuclear receptor related 1 (NURR1; NR4A2)
- 3: Neuron-derived orphan receptor 1 (NOR1; NR4A3)
Subfamily 5: Steroidogenic Factor-like
- Group A: SF1/LRH1
- 1: Steroidogenic factor 1 (SF1; NR5A1)
- 2: Liver receptor homolog-1 (LRH-1; NR5A2)
Subfamily 6: Germ Cell Nuclear Factor-like
- Group A: GCNF
- 1: Germ cell nuclear factor (GCNF; NR6A1)
Subfamily 0: Miscellaneous
- Group B: DAX/SHP
- 1: Dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1 (DAX1, NR0B1)
- 2: Small heterodimer partner (SHP; NR0B2)
- Group C: Nuclear receptors with two DNA binding domains (2DBD-NR) (A novel subfamily)
History of nuclear receptors
Below is a brief selection of key events in the history of nuclear receptor research.
- 1905 - Ernest Starling coined the word hormone
- 1926 - Edward Calvin Kendall and Tadeus Reichstein isolated and determined the structures of cortisone and thyroxine
- 1929 - Adolf Butenandt and Edward Adelbert Doisy - independently isolated and determined the structure of estrogen
- 1961 - Elwood 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
- ^ Evans RM (1988). "The steroid and thyroid hormone receptor superfamily". Science 240 (4854): 889-95. doi:10.1126/science.3283939. PMID 3283939.
- ^ Olefsky JM (2001). "Nuclear receptor minireview series". J. Biol. Chem. 276 (40): 36863-4. doi:10.1074/jbc.R100047200. PMID 11459855.
- ^ a b Mangelsdorf DJ, Thummel C, Beato M, Herrlich P, Schutz G, Umesono K, Blumberg B, Kastner P, Mark M, Chambon P, Evans RM (1995). "The nuclear receptor superfamily: the second decade". Cell 83 (6): 835-9. doi:10.1016/0092-8674(95)90199-X. PMID 8521507.
- ^ a b Novac N, Heinzel T (2004). "Nuclear receptors: overview and classification". Curr Drug Targets Inflamm Allergy 3 (4): 335-46. PMID 15584884.
- ^ a b c Nuclear Receptors Nomenclature Committee (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.
- ^ a b Laudet V (1997). "Evolution of the nuclear receptor superfamily: early diversification from an ancestral orphan receptor". J. Mol. Endocrinol. 19 (3): 207-26. doi:10.1677/jme.0.0190207. PMID 9460643.
- ^ Overington JP, Al-Lazikani B, Hopkins AL (2006). "How many drug targets are there?". Nature reviews. Drug discovery 5 (12): 993-6. doi:10.1038/nrd2199. PMID 17139284.
- ^ Benoit G, Cooney A, Giguere V, Ingraham H, Lazar M, Muscat G, Perlmann T, Renaud JP, Schwabe J, Sladek F, Tsai MJ, Laudet V (2006). "International Union of Pharmacology. LXVI. Orphan nuclear receptors". Pharmacol. Rev. 58 (4): 798-836. doi:10.1124/pr.58.4.10. PMID 17132856.
- ^ Mohan R, Heyman RA (2003). "Orphan nuclear receptor modulators". Curr Top Med Chem 3 (14): 1637-47. doi:10.2174/1568026033451709. PMID 14683519.
- ^ Kumar R, Thompson EB (1999). "The structure of the nuclear hormone receptors". Steroids 64 (5): 310–9. doi:10.1016/S0039-128X(99)00014-8. PMID 10406480.
- ^ Klinge CM (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.
- ^ a b Wärnmark A, Treuter E, Wright AP, Gustafsson J-Å (2003). "Activation functions 1 and 2 of nuclear receptors: molecular strategies for transcriptional activation". Mol. Endocrinol. 17 (10): 1901-9. doi:10.1210/me.2002-0384. PMID 12893880.
- ^ Glass CK, Rosenfeld MG (2000). "The coregulator exchange in transcriptional functions of nuclear receptors". Genes Dev 14 (2): 121-41. doi:10.1101/gad.14.2.121. PMID 10652267.
- ^ Aranda A, Pascual A (2001). "Nuclear hormone receptors and gene expression". Physiol. Rev. 81 (3): 1269-304. PMID 11427696.
- ^ Brzozowski AM, Pike AC, Dauter Z, Hubbard RE, Bonn T, Engström O, Öhman L, Greene GL, Gustafsson J-Å, Carlquist M (1997). "Molecular basis of agonism and antagonism in the oestrogen receptor". Nature 389 (6652): 753-8. doi:10.1038/39645. PMID 9338790.
- ^ Shiau AK, Barstad D, Loria PM, Cheng L, Kushner PJ, Agard DA, Greene GL (1998). "The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen". Cell 95 (7): 927-37. doi:10.1016/S0092-8674(00)81717-1. PMID 9875847.
- ^ Gronemeyer H, Gustafsson JA, Laudet V (2004). "Principles for modulation of the nuclear receptor superfamily". Nature reviews. Drug discovery 3 (11): 950-64. doi:10.1038/nrd1551. PMID 15520817.
- ^ Smith CL, O'Malley BW (2004). "Coregulator function: a key to understanding tissue specificity of selective receptor modulators". Endocr Rev 25 (1): 45-71. doi:10.1210/er.2003-0023. PMID 14769827.
- ^ Pascual G, Glass CK (2006). "Nuclear receptors versus inflammation: mechanisms of transrepression". Trends Endocrinol Metab 17 (8): 321-7. doi:10.1016/j.tem.2006.08.005. PMID 16942889.
- ^ Björnström L, Sjöberg M (2004). "Estrogen receptor-dependent activation of AP-1 via non-genomic signalling". Nucl Recept 2 (1): 3. doi:10.1186/1478-1336-2-3. PMID 15196329.
- ^ Zivadinovic D, Gametchu B, Watson CS (2005). "Membrane estrogen receptor-alpha levels in MCF-7 breast cancer cells predict cAMP and proliferation responses". Breast Cancer Res. 7 (1): R101-12. doi:10.1186/bcr958. PMID 15642158.
- ^ Zhang Z, Burch PE, Cooney AJ, Lanz RB, Pereira FA, Wu J, Gibbs RA, Weinstock G, Wheeler DA (2004). "Genomic analysis of the nuclear receptor family: new insights into structure, regulation, and evolution from the rat genome". Genome Res 14 (4): 580-90. doi:10.1101/gr.2160004. PMID 15059999.
- ^ Wu W, Niles EG, El-Sayed N, Berriman M, LoVerde PT (2006). "Schistosoma mansoni (Platyhelminthes, Trematoda) nuclear receptors: sixteen new members and a novel subfamily". Gene 366 (2): 303-15. doi:10.1016/j.gene.2005.09.013. PMID 16406405.
- ^ Wu W, Niles EG, Hirai H, LoVerde PT (2004). "Evolution of a novel subfamily of nuclear receptors with members that each contain two DNA binding domains". BMC Evol Biol 7 (Feb 23): 27. doi:10.1186/1471-2148-7-27. PMID 17319953.
- ^ Tata JR (2005). "One hundred years of hormones". EMBO Rep. 6 (6): 490-6. doi:10.1038/sj.embor.7400444. PMID 15940278.
|Transcription factors and intracellular receptors|
|(1) Basic domains|
|(1.1) Basic leucine zipper (bZIP)
||Activating transcription factor (1, 2, 3, 4, 5, 6) • AP-1 (c-Fos, FOSB, FOSL1, FOSL2, c-Jun, JUNB, JUND) • BACH (1, 2) • C/EBP (α, β, γ, δ, ε, ζ) • CREB (1, 3) • GABPA • MAF (B, F, G, K) • NRL • NRF1 • XBP1
|(1.2) Basic helix-loop-helix (bHLH)
||ATOH1 • AhR • AHRR • ARNT • ASCL1 • BMAL (ARNTL, ARNTL2) • CLOCK • HIF (1A, 3A) • Myogenic regulatory factors (MyoD, Myogenin, MYF5, MYF6) • NEUROD1 • Twist • USF1
||Myc • MITF • SREBP (1, 2)
|(1.6) Basic helix-span-helix (bHSH)
|(2) Zinc finger|
|(2.1) Nuclear receptor (Cys4)
||subfamily 1 (Thyroid hormone (α, β), CAR, FXR, LXR (α, β), PPAR (α, β/δ, γ), PXR, RAR (α, β, γ), ROR (α, β, γ), Rev-ErbA (α, β), VDR) • subfamily 2 (COUP-TF (I, II), Ear-2, HNF4 (α, γ), PNR, RXR (α, β, γ), Testicular receptor (2, 4), TLX) • subfamily 3 (Steroid hormone (Estrogen (α, β), Estrogen related (α, β, γ), Androgen, Glucocorticoid, Mineralocorticoid, Progesterone)) • subfamily 4 NUR (NGFIB, NOR1, NURR1) • subfamily 5 (LRH-1, SF1) • subfamily 6 (GCNF) • subfamily 0 (DAX1, SHP)
|(2.2) Other Cys4
||GATA (1, 2, 3, 4, 5, 6)
||General transcription factors (TFIIA, TFIIB, TFIID, TFIIE, TFIIF, TFIIH: 1, 2) • GLI-Krüppel family (1, 2, 3, YY1) • KLF (2, 4, 5, 6, 10, 11, 12, 13) • Sp1 • zinc finger (3, 35, 43, 146, 148, 165, 217, 268, 281, 350) • Zbtb7 (7A) • ZBT (16, 17, 33)
|(3.1) Homeo domain
||ARX • Homeobox (A1, A3, A4, A5, A7, A9, A10, A11, A13, B1, B2, B3, B4, B5, B6, B7, B8, B9, B13, C4, C6, C8, C9, C13, D1, D3, D4, D9, D10, D11, D12, D13) • NANOG • NKX (2-1, 2-5, 3-1) • POU domain (PIT-1, BRN-3: 1, 2, Octamer transcription factor: 1, 2, 3/4, 6, 7)
|(3.2) Paired box
||PAX (1, 2, 3, 4, 5, 6, 7, 8, 9)
|(3.3) Fork head / winged helix
||E2F (1, 2, 3, 4, 5) • FOX proteins (C1, C2, E1, G1, H1, L2, M1, N3, O3, O4, P1, P2, P3)
|(3.4) Heat Shock Factors
|(3.5) Tryptophan clusters
||ELF (4, 5) • Interferon regulatory factors (1, 2, 3, 4, 5, 6, 7, 8) • MYB
|(3.6) TEA domain
||transcriptional enhancer factor 1, 2
|(4) β-Scaffold factors with|
minor groove contacts
|(4.1) Rel homology region
||NF-κB (NFKB1, NFKB2, REL, RELA, RELB) • NFAT (5, C1, C2, C3, C4)
||STAT (1, 2, 3, 4, 5, 6)
|(4.4) MADS box
||Mef2 (A, B, C, D) • SRF
|(4.7) High mobility group
||HNF (1A, 1B) • LEF1 • SOX (3, 4, 6, 9, 10, 13, 18) • SRY • SSRP1
|(4.10) Cold-shock domain
||CBF (RUNX1, RUNX2, RUNX3)
| (0) Other|
||HMGA (1, 2)
|(0.3) Pocket domain
||Rb • RBL1 • RBL2
||ARID (1A, 1B, 2, 3A, 3B, 4A) • CAP • Rho/Sigma • R-SMAD