c4 zinc finger in nuclear hormone receptors;

                           10        20        30        40        50        60        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71984640    146 CVGCGsESAIRVHYGASSCHGCKAFFRRSVFEGRVYMCSADNHCDITNESRNRCRACRLRNCLEGGMNPK 215
Cdd:smart00399   2 CCVCG-DHASGFHFGVCSCRACKAFFRRTVNLRYKYRCDRKNNCSINKRYRCRCRACRLKKCLGVGMDPE 70

c4 zinc finger in nuclear hormone receptors;

                           10        20        30        40        50        60        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71984640    146 CVGCGsESAIRVHYGASSCHGCKAFFRRSVFEGRVYMCSADNHCDITNESRNRCRACRLRNCLEGGMNPK 215
Cdd:smart00399   2 CCVCG-DHASGFHFGVCSCRACKAFFRRTVNLRYKYRCDRKNNCSINKRYRCRCRACRLKKCLGVGMDPE 70

DNA-binding domain of heptocyte nuclear factor 4 (HNF4) is composed of two C4-type zinc fingers; DNA-binding domain of hepatocyte nuclear factor 4 (HNF4) is composed of two C4-type zinc fingers. Each zinc finger contains a group of four Cys residues which co-ordinates a single zinc atom. HNF4 interacts with a DNA site, composed of two direct repeats of AGTTCA with 1 bp spacer, which is upstream of target genes and modulates the rate of transcriptional initiation. HNF4 is a member of the nuclear receptor superfamily. HNF4 plays a key role in establishing and maintenance of hepatocyte differentiation in the liver. It is also expressed in gut, kidney, and pancreatic beta cells. HNF4 was originally classified as an orphan receptor, but later it is found that HNF4 binds with very high affinity to a variety of fatty acids. However, unlike other nuclear receptors, the ligands do not act as a molecular switch for HNF4. They seem to constantly bind to the receptor, which is constitutively active as a transcription activator. Like other members of the nuclear receptor (NR) superfamily of ligand-activated transcription factors, HNF4 has a central well conserved DNA binding domain (DBD), a variable N-terminal domain, a flexible hinge and a C-terminal ligand binding domain (LBD).

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 71984640 146 CVGCGSESAIRvHYGASSCHGCKAFFRRSVFEGRVYMCSADNHCDITNESRNRCRACRLRNCLEGGMNPKHVREERS 222
Cdd:cd06960   1 CAVCGDRATGK-HYGVLSCNGCKGFFRRSVRKNRTYTCRFGGNCVVDKDKRNACRYCRFKKCLEVGMDPEAVQNERD 76

Ligand-binding domain of nuclear hormone receptor; This all helical domain is involved in binding the hormone in these receptors.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71984640   365 DLYLSWYRSFVFAADWAMGIPEFRVLPLADQTTLFKQNFMAFGWITFAYKCFELKQHLT----GMPLGNGAYIPYNDEDQ 440
Cdd:pfam00104  15 ELCELWERDLLLVAEWAKHFPEFQELPLEDQMALLKSFWLEWLRLEKAARSAKLRRKKIlgedVLMISDDDAMKFVEDDS 94

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71984640   441 K---KLPERWAQTYGVVCRKLIDLIVKAMIELQITEEEYCLIKTISLFQQD-CILSEAGQGICSRMRDRLLDALSAHIEK 516
Cdd:pfam00104  95 SwctNYDLEQLLFFLPFFNSYFFELVKPLRELNPDDEELAYLLAQLLFDYAgDGLSGEILEIVEKLQEKLANELHDYYVN 174

                         170       180
                  ....*....|....*....|....*..
gi 71984640   517 RYPyhttsQRMTRALKIslmLPSFSHI 543
Cdd:pfam00104 175 KYS-----GRLAKLLKI---LPSLRKI 193

c4 zinc finger in nuclear hormone receptors;

                           10        20        30        40        50        60        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71984640    146 CVGCGsESAIRVHYGASSCHGCKAFFRRSVFEGRVYMCSADNHCDITNESRNRCRACRLRNCLEGGMNPK 215
Cdd:smart00399   2 CCVCG-DHASGFHFGVCSCRACKAFFRRTVNLRYKYRCDRKNNCSINKRYRCRCRACRLKKCLGVGMDPE 70

DNA-binding domain of heptocyte nuclear factor 4 (HNF4) is composed of two C4-type zinc fingers; DNA-binding domain of hepatocyte nuclear factor 4 (HNF4) is composed of two C4-type zinc fingers. Each zinc finger contains a group of four Cys residues which co-ordinates a single zinc atom. HNF4 interacts with a DNA site, composed of two direct repeats of AGTTCA with 1 bp spacer, which is upstream of target genes and modulates the rate of transcriptional initiation. HNF4 is a member of the nuclear receptor superfamily. HNF4 plays a key role in establishing and maintenance of hepatocyte differentiation in the liver. It is also expressed in gut, kidney, and pancreatic beta cells. HNF4 was originally classified as an orphan receptor, but later it is found that HNF4 binds with very high affinity to a variety of fatty acids. However, unlike other nuclear receptors, the ligands do not act as a molecular switch for HNF4. They seem to constantly bind to the receptor, which is constitutively active as a transcription activator. Like other members of the nuclear receptor (NR) superfamily of ligand-activated transcription factors, HNF4 has a central well conserved DNA binding domain (DBD), a variable N-terminal domain, a flexible hinge and a C-terminal ligand binding domain (LBD).

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 71984640 146 CVGCGSESAIRvHYGASSCHGCKAFFRRSVFEGRVYMCSADNHCDITNESRNRCRACRLRNCLEGGMNPKHVREERS 222
Cdd:cd06960   1 CAVCGDRATGK-HYGVLSCNGCKGFFRRSVRKNRTYTCRFGGNCVVDKDKRNACRYCRFKKCLEVGMDPEAVQNERD 76

DNA-binding domain of nuclear receptors is composed of two C4-type zinc fingers; DNA-binding domain of nuclear receptors is composed of two C4-type zinc fingers. Each zinc finger contains a group of four Cys residues which co-ordinates a single zinc atom. It interacts with a specific DNA site upstream of the target gene and modulates the rate of transcriptional initiation. Nuclear receptors form a superfamily of ligand-activated transcription regulators, which regulate various physiological functions, from development, reproduction, to homeostasis and metabolism in animals (metazoans). The family contains not only receptors for known ligands but also orphan receptors for which ligands do not exist or have not been identified. NRs share a common structural organization with a central well conserved DNA binding domain (DBD), a variable N-terminal domain, a flexible hinge and a C-terminal ligand binding domain (LBD). Most nuclear receptors bind as homodimers or heterodimers to their target sites, which consist of two hexameric half-sites. Specificity is determined by the half-site sequence, the relative orientation of the half-sites and the number of spacer nucleotides between the half-sites. However, a growing number of nuclear receptors have been reported to bind to DNA as monomers.

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 71984640 146 CVGCGSESAIRvHYGASSCHGCKAFFRRSVFEGRVYMCSADNHCDITNESRNRCRACRLRNCLEGGMNPKHVR 218
Cdd:cd06916   1 CAVCGDKASGY-HYGVLTCEGCKGFFRRSVRRNLEYTCPAGGNCVIDKRNRNRCQACRLKKCLAVGMRKEAVR 72

DNA-binding domain of the TR2 and TR4 (human testicular receptor 2 and 4) is composed of two C4-type zinc fingers; DNA-binding domain of the TR2 and TR4 (human testicular receptor 2 and 4) is composed of two C4-type zinc fingers. Each zinc finger contains a group of four Cys residues which coordinates a single zinc atom. TR2 and TR4 interact with specific DNA sites upstream of the target gene and modulate the rate of transcriptional initiation. TR4 and TR2 are orphan nuclear receptors; the physiological ligand is as yet unidentified. TR2 is abundantly expressed in the androgen-sensitive prostate. TR4 transcripts are expressed in many tissues, including central nervous system, adrenal gland, spleen, thyroid gland, and prostate. It has been shown that human TR2 binds to a wide spectrum of natural hormone response elements (HREs) with distinct affinities suggesting that TR2 may cross-talk with other gene expression regulation systems. The genes responding to TR2 or TR4 include genes that are regulated by retinoic acid receptor, vitamin D receptor, and peroxisome proliferator-activated receptor. TR4/2 binds to HREs as dimers. Like other members of the nuclear receptor (NR) superfamily of ligand-activated transcription factors, TR2-like receptors have a central well conserved DNA binding domain (DBD), a variable N-terminal domain, a flexible hinge and a C-terminal ligand binding domain (LBD).

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71984640 143 GERCVGCGSESAIRvHYGASSCHGCKAFFRRSVFEGRVYMCSADNHCDITNESRNRCRACRLRNCLEGGMNPKHVREERS 222
Cdd:cd06967   3 VELCVVCGDKASGR-HYGAVSCEGCKGFFKRSIRKNLGYSCRGSKDCVINKHHRNRCQYCRLQKCLAMGMKSDSVQCERK 81

                ...
gi 71984640 223 KIE 225
Cdd:cd06967  82 PID 84

DNA-binding domain of thyroid hormone receptors (TRs) is composed of two C4-type zinc fingers; DNA-binding domain of thyroid hormone receptors (TRs) is composed of two C4-type zinc fingers. Each zinc finger contains a group of four Cys residues which co-ordinates a single zinc atom. TR interacts with the thyroid response element, which is a DNA site with direct repeats of the consensus sequence 5'-AGGTCA-3' separated by one to five base pairs, upstream of target genes and modulates the rate of transcriptional initiation. Thyroid hormone receptor (TR) mediates the actions of thyroid hormones, which play critical roles in growth, development, and homeostasis in mammals. They regulate overall metabolic rate, cholesterol and triglyceride levels, and heart rate, and affect mood. TRs are expressed from two separate genes (alpha and beta) in human and each gene generates two isoforms of the receptor through differential promoter usage or splicing. TRalpha functions in the heart to regulate heart rate and rhythm and TRbeta is active in the liver and other tissues. The unliganded TRs function as transcription repressors, by binding to thyroid hormone response elements (TRE) predominantly as homodimers, or as heterodimers with retinoid X-receptors (RXR), and being associated with a complex of proteins containing corepressor proteins. Ligand binding promotes corepressor dissociation and binding of a coactivator to activate transcription. Like other members of the nuclear receptor (NR) superfamily of ligand-activated transcription factors, TR has a central well conserved DNA binding domain (DBD), a variable N-terminal domain, a flexible hinge and a C-terminal ligand binding domain (LBD).

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71984640 146 CVGCGsESAIRVHYGASSCHGCKAFFRRSVFEGRVYMCSADNHCDITNESRNRCRACRLRNCLEGGMNPKHVREERSKIE 225
Cdd:cd06961   2 CVVCG-DKATGYHYRCITCEGCKGFFRRTVQKKLSYSCKGEGKCEIDKVTRNQCQECRFKKCIAVGMAKDLVLDDRKRGA 80

                .
gi 71984640 226 R 226
Cdd:cd06961  81 K 81

Ligand-binding domain of nuclear hormone receptor; This all helical domain is involved in binding the hormone in these receptors.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71984640   365 DLYLSWYRSFVFAADWAMGIPEFRVLPLADQTTLFKQNFMAFGWITFAYKCFELKQHLT----GMPLGNGAYIPYNDEDQ 440
Cdd:pfam00104  15 ELCELWERDLLLVAEWAKHFPEFQELPLEDQMALLKSFWLEWLRLEKAARSAKLRRKKIlgedVLMISDDDAMKFVEDDS 94

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71984640   441 K---KLPERWAQTYGVVCRKLIDLIVKAMIELQITEEEYCLIKTISLFQQD-CILSEAGQGICSRMRDRLLDALSAHIEK 516
Cdd:pfam00104  95 SwctNYDLEQLLFFLPFFNSYFFELVKPLRELNPDDEELAYLLAQLLFDYAgDGLSGEILEIVEKLQEKLANELHDYYVN 174

                         170       180
                  ....*....|....*....|....*..
gi 71984640   517 RYPyhttsQRMTRALKIslmLPSFSHI 543
Cdd:pfam00104 175 KYS-----GRLAKLLKI---LPSLRKI 193

DNA-binding domain of Drosophila ecdysone-induced protein 78 (E78) like is composed of two C4-type zinc fingers; DNA-binding domain of proteins similar to Drosophila ecdysone-induced protein 78 (E78) is composed of two C4-type zinc fingers. Each zinc finger contains a group of four Cys residues which coordinates a single zinc atom. E78 interacts with specific DNA sites upstream of the target gene and modulates the rate of transcriptional initiation. Drosophila ecdysone-induced protein 78 (E78) is a transcription factor belonging to the nuclear receptor superfamily. E78 is a product of the ecdysone-inducible gene found in an early late puff locus at position 78C during the onset of Drosophila metamorphosis. An E78 orthologue from the Platyhelminth Schistosoma mansoni (SmE78) has also been identified. It is the first E78 orthologue known outside of the molting animals--the Ecdysozoa. The SmE78 may be involved in transduction of an ecdysone signal in S. mansoni, consistent with its function in Drosophila. Like other members of the nuclear receptor (NR) superfamily of ligand-activated transcription factors, E78-like receptors have a central well conserved DNA-binding domain (DBD), a variable N-terminal domain, a non-conserved hinge and a C-terminal ligand binding domain (LBD).

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 71984640 146 CVGCGSESAiRVHYGASSCHGCKAFFRRSVFEGRVYMCSADNHCDITNESRNRCRACRLRNCLEGGMNPKHVREER 221
Cdd:cd07165   1 CKVCGDKAS-GYHYGVTSCEGCKGFFRRSIQKQIEYRCLRDGKCEIIRLNRNRCQYCRFKKCLAAGMSKDSVRYGR 75

DNA-binding domain of the orphan nuclear receptor, nerve growth factor-induced-B; DNA-binding domain (DBD) of the orphan nuclear receptor, nerve growth factor-induced-B (NGFI-B) is composed of two C4-type zinc fingers. Each zinc finger contains a group of four Cys residues which co-ordinates a single zinc atom. NGFI-B interacts with specific DNA sites upstream of the target gene and modulates the rate of transcriptional initiation. NGFI-B is a member of the nuclear-steroid receptor superfamily. NGFI-B is classified as an orphan receptor because no ligand has yet been identified. NGFI-B is an early immediate gene product of embryo development that is rapidly produced in response to a variety of cellular signals including nerve growth factor. It is involved in T-cell-mediated apoptosis, as well as neuronal differentiation and function. NGFI-B regulates transcription by binding to a specific DNA target upstream of its target genes and regulating the rate of transcriptional initiation. NGFI-B binds to the NGFI-B response element (NBRE) 5'-(A/T)AAAGGTCA as a monomer. Like other members of the nuclear receptor (NR) superfamily of ligand-activated transcription factors, NGFI-B has a central well-conserved DNA binding domain (DBD), a variable N-terminal domain, a flexible hinge and a C-terminal ligand binding domain (LBD).

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 71984640 144 ERCVGCGSESAIRvHYGASSCHGCKAFFRRSVFEGRVYMCSADNHCDITNESRNRCRACRLRNCLEGGMNPKHVR 218
Cdd:cd06969   1 GLCAVCGDNAACQ-HYGVRTCEGCKGFFKRTVQKNAKYVCLANKNCPVDKRRRNRCQYCRFQKCLQVGMVKEVVR 74

The second DNA-binding domain (DBD) of the 2DBD nuclear receptor is composed of two C4-type zinc fingers; The second DNA-binding domain (DBD) of the 2DBD nuclear receptor (NR) is composed of two C4-type zinc fingers. Each zinc finger contains a group of four Cys residues which co-ordinates a single zinc atom. NRs interact with specific DNA sites upstream of the target gene and modulate the rate of transcriptional initiation. The proteins contain two DBDs in tandem, probably resulting from an ancient recombination event. The 2DBD-NRs are found only in flatworm species, mollusks and arthropods. Their biological function is unknown.

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 71984640 146 CVGCGSESAiRVHYGASSCHGCKAFFRRSVFEGRVYMCSADNHCDITNESRNRCRACRLRNCLEGGMNPKHVR 218
Cdd:cd07179   1 CRVCGGKSS-GFHFGALTCEGCKGFFRRTELSSNSYVCPGGQNCAITPATRNACKSCRFRRCLAVGMSKTGSR 72

The DNA-binding domain of the photoreceptor cell-specific nuclear receptor (PNR) nuclear receptor-like family; The DNA-binding domain of the photoreceptor cell-specific nuclear receptor (PNR) nuclear receptor-like family is composed of two C4-type zinc fingers. Each zinc finger contains a group of four Cys residues which coordinates a single zinc atom. PNR interacts with specific DNA sites upstream of the target gene and modulates the rate of transcriptional initiation. This family includes nuclear receptor Tailless (TLX), photoreceptor cell-specific nuclear receptor (PNR) and related receptors. TLX is an orphan receptor that plays a key role in neural development by regulating cell cycle progression and exit of neural stem cells in the developing brain. PNR is expressed only in the outer layer of retinal photoreceptor cells. It may be involved in the signaling pathway regulating photoreceptor differentiation and/or maintenance. Like other members of the nuclear receptor (NR) superfamily of ligand-activated transcription factors, PNR-like receptors have a central well-conserved DNA-binding domain (DBD), a variable N-terminal domain, a flexible hinge and a C-terminal ligand binding domain (LBD).

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 71984640 146 CVGCGSESAIRvHYGASSCHGCKAFFRRSVFEGRVYMCSADN-HCDITNESRNRCRACRLRNCLEGGMNPKHVR 218
Cdd:cd07154   1 CKVCGDRSSGK-HYGVYACDGCSGFFKRSIRRNLLYTCKAGNgSCVVDKARRNQCQACRLKKCLEVSMNKDAVQ 73

DNA-binding domain of the photoreceptor cell-specific nuclear receptor (PNR) is composed of two C4-type zinc fingers; DNA-binding domain of the photoreceptor cell-specific nuclear receptor (PNR) is composed of two C4-type zinc fingers. Each zinc finger contains a group of four Cys residues which co-ordinates a single zinc atom. PNR interacts with specific DNA sites upstream of the target gene and modulates the rate of transcriptional initiation. PNR is a member of the nuclear receptor superfamily of the ligand-activated transcription factors. PNR is expressed only in the outer layer of retinal photoreceptor cells. It may be involved in the signaling pathway regulating photoreceptor differentiation and/or maintenance. It most likely binds to DNA as a homodimer. Like other members of the nuclear receptor (NR) superfamily of ligand-activated transcription factors, PNR has a central well conserved DNA binding domain (DBD), a variable N-terminal domain, a flexible hinge and a C-terminal ligand binding domain (LBD).

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71984640 146 CVGCGSESAIRvHYGASSCHGCKAFFRRSVFEGRVYMCSADN-HCDITNESRNRCRACRLRNCLEGGMNPKHVREERSki 224
Cdd:cd06970   9 CRVCGDTSSGK-HYGIYACNGCSGFFKRSVRRKLIYRCQAGTgMCPVDKAHRNQCQACRLKKCLQAGMNKDAVQNERQ-- 85

                        90
                ....*....|
gi 71984640 225 ermPGNTCTV 234
Cdd:cd06970  86 ---PRNTAQV 92

DNA-binding domain of Liver X receptors (LXRs) family is composed of two C4-type zinc fingers; DNA-binding domain of Liver X receptors (LXRs) family is composed of two C4-type zinc fingers. Each zinc finger contains a group of four Cys residues which co-ordinates a single zinc atom. LXR interacts with specific DNA sites upstream of the target gene and modulates the rate of transcriptional initiation. LXR operates as cholesterol sensor which protects cells from cholesterol overload by stimulating reverse cholesterol transport from peripheral tissues to the liver and its excretion in the bile. Oxidized cholesterol derivatives or oxysterols were identified as specific ligands for LXRs. LXR functions as a heterodimer with the retinoid X receptor (RXR) which may be activated by either LXR agonist or 9-cis retinoic acid, a specific RXR ligand. The LXR/RXR complex binds to a liver X receptor response element (LXRE) in the promoter region of target genes. The ideal LXRE sequence is a direct repeat-4 (DR-4) DNA fragment consisting of two AGGTCA hexameric half-sites separated by a 4-nucleotide spacer. LXR has typical NR modular structure with a central well conserved DNA binding domain (DBD), a variable N-terminal domain, a flexible hinge and the ligand binding domain (LBD) at the C-terminal.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71984640 138 PNVIKGERCVGCGsESAIRVHYGASSCHGCKAFFRRSVFEGRVYMCSADNHCDITNESRNRCRACRLRNCLEGGMNPKHV 217
Cdd:cd07160  13 PKMLGNEVCSVCG-DKASGFHYNVLSCEGCKGFFRRSVIKGAQYVCKNGGKCQMDMYMRRKCQECRLRKCREAGMREQCV 91

                        90
                ....*....|
gi 71984640 218 -REERSKIER 226
Cdd:cd07160  92 lSEEQIRLKK 101

DNA-binding domain of Retinoid-related orphan receptors (RORs) is composed of two C4-type zinc fingers; DNA-binding domain of Retinoid-related orphan receptors (RORs) is composed of two C4-type zinc fingers. Each zinc finger contains a group of four Cys residues which coordinates a single zinc atom. ROR interacts with specific DNA sites upstream of the target gene and modulates the rate of transcriptional initiation. RORS are key regulators of many physiological processes during embryonic development. RORs bind as monomers to specific ROR response elements (ROREs) consisting of the consensus core motif AGGTCA preceded by a 5-bp A/T-rich sequence. There are three subtypes of retinoid-related orphan receptors (RORs), alpha, beta, and gamma, which differ only in N-terminal sequence and are distributed in distinct tissues. RORalpha plays a key role in the development of the cerebellum particularly in the regulation of the maturation and survival of Purkinje cells. RORbeta expression is largely restricted to several regions of the brain, the retina, and pineal gland. RORgamma is essential for lymph node organogenesis. Recently, it has been suggested that cholesterol or a cholesterol derivative are the natural ligands of RORalpha. Like other members of the nuclear receptor (NR) superfamily of ligand-activated transcription factors, retinoid-related orphan receptors have a central well conserved DNA binding domain (DBD), a variable N-terminal domain, a non-conserved hinge and a C-terminal ligand binding domain (LBD).

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71984640 146 CVGCGSESAiRVHYGASSCHGCKAFFRRSVFEGRVYMCSADNHCDITNESRNRCRACRLRNCLEGGMN---PKHVREERS 222
Cdd:cd06968   8 CKICGDKSS-GIHYGVITCEGCKGFFRRSQQNNVSYSCPRQKNCLIDRTNRNRCQHCRLQKCLALGMSrdaVKFGRMSKK 86

                ....*....
gi 71984640 223 KIERMPGNT 231
Cdd:cd06968  87 QRDSLYAEV 95

The DNA-binding domain of Lrh-1 like nuclear receptor family like is composed of two C4-type zinc fingers; The DNA-binding domain of Lrh-1 like nuclear receptor family like is composed of two C4-type zinc fingers. Each zinc finger contains a group of four Cys residues which co-ordinates a single zinc atom. This domain interacts with specific DNA sites upstream of the target gene and modulates the rate of transcriptional initiation. This nuclear receptor family includes at least three subgroups of receptors that function in embryo development and differentiation, and other processes. FTZ-F1 interacts with the cis-acting DNA motif of ftz gene, which is required at several stages of development. Particularly, FTZ-F1 regulated genes are strongly linked to steroid biosynthesis and sex-determination; LRH-1 is a regulator of bile-acid homeostasis, steroidogenesis, reverse cholesterol transport and the initial stages of embryonic development; SF-1 is an essential regulator of endocrine development and function and is considered a master regulator of reproduction; SF-1 functions cooperatively with other transcription factors to modulate gene expression. Phospholipids have been identified as potential ligand for LRH-1 and steroidogenic factor-1 (SF-1). However, the ligand for FTZ-F1 has not yet been identified. Most nuclear receptors function as homodimer or heterodimers. However, LRH-1 and SF-1 bind to DNA as monomers. Like other members of the nuclear receptor (NR) superfamily of ligand-activated transcription factors, receptors in this family have a central well conserved DNA-binding domain (DBD), a variable N-terminal domain, a flexible hinge and a C-terminal ligand binding domain (LBD).

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 71984640 158 HYGASSCHGCKAFFRRSVFEGRVYMCSADNHCDITNESRNRCRACRLRNCLEGGMNPKHVREERSK 223
Cdd:cd07167  12 HYGLLTCESCKGFFKRTVQNKKRYTCIENQNCQIDKTQRKRCPYCRFQKCLSVGMKLEAVRADRMR 77

The DNA-binding domain of vitamin D receptors (VDR) like nuclear receptor family is composed of two C4-type zinc fingers; The DNA-binding domain of vitamin D receptors (VDR) like nuclear receptor family is composed of two C4-type zinc fingers. Each zinc finger contains a group of four Cys residues which co-ordinates a single zinc atom. This domain interacts with specific DNA site upstream of the target gene and modulates the rate of transcriptional initiation. This family includes three types of nuclear receptors: vitamin D receptors (VDR), constitutive androstane receptor (CAR) and pregnane X receptor (PXR). VDR regulates calcium metabolism, cellular proliferation and differentiation. PXR and CAR function as sensors of toxic byproducts of cell metabolism and of exogenous chemicals, to facilitate their elimination. The DNA binding activity is regulated by their corresponding ligands. VDR is activated by Vitamin D; CAR and PXR respond to a diverse array of chemically distinct ligands, including many endogenous compounds and clinical drugs. Like other nuclear receptors, xenobiotic receptors have a central well conserved DNA binding domain (DBD), a variable N-terminal domain, a flexible hinge and a C-terminal ligand binding domain (LBD).

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 71984640 146 CVGCGsESAIRVHYGASSCHGCKAFFRRSVFEGRVYMCSADNHCDITNESRNRCRACRLRNCLEGGM 212
Cdd:cd07156   1 CGVCG-DRATGYHFNAMTCEGCKGFFRRSMKRKARFTCPFNGDCEITKDNRRHCQACRLKKCLDIGM 66

DNA-binding domain of REV-ERB receptor-like is composed of two C4-type zinc fingers; DNA-binding domain of REV-ERB receptor- like is composed of two C4-type zinc fingers. Each zinc finger contains a group of four Cys residues which coordinates a single zinc atom. This domain interacts with specific DNA sites upstream of the target gene and modulates the rate of transcriptional initiation. REV-ERB receptors are transcriptional regulators belonging to the nuclear receptor superfamily. They regulate a number of physiological functions including the circadian rhythm, lipid metabolism, and cellular differentiation. REV-ERB receptors bind as a monomer to a (A/G)GGTCA half-site with a 5' AT-rich extension or as a homodimer to a direct repeat 2 element (AGGTCA sequence with a 2-bp spacer), indicating functional diversity. When bound to the DNA, they recruit corepressors (NcoR/histone deacetylase 3) to the promoter, resulting in repression of the target genes. The porphyrin heme has been demonstrated to function as a ligand for REV-ERB receptor. Like other members of the nuclear receptor (NR) superfamily of ligand-activated transcription factors, REV-ERB receptors have a central well conserved DNA binding domain (DBD), a variable N-terminal domain, a non-conserved hinge and a C-terminal ligand binding domain (LBD).

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 71984640 146 CVGCGSESAiRVHYGASSCHGCKAFFRRSVFEGRVY-MCSADNHCDITNESRNRCRACRLRNCLEGGMNPKHVREER 221
Cdd:cd07166   6 CKVCGDKAS-GFHYGVHACEGCKGFFRRSIQQKIQYrKCTKNETCSIMRINRNRCQYCRFKKCLAVGMSRDAVRFGR 81

The DNA-binding domain of peroxisome proliferator-activated receptors (PPAR) like nuclear receptor family; The DNA-binding domain of peroxisome proliferator-activated receptors (PPAR) like nuclear receptor family is composed of two C4-type zinc fingers. Each zinc finger contains a group of four Cys residues which co-ordinates a single zinc atom. These domains interact with specific DNA sites upstream of the target gene and modulate the rate of transcriptional initiation. This family includes three known types of nuclear receptors: peroxisome proliferator-activated receptors (PPAR), REV-ERB receptors and Drosophila ecdysone-induced protein 78 (E78). Like other members of the nuclear receptor (NR) superfamily of ligand-activated transcription factors, PPAR-like receptors have a central well conserved DNA binding domain (DBD), a variable N-terminal domain, a non-conserved hinge and a C-terminal ligand binding domain (LBD).

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 71984640 146 CVGCGsESAIRVHYGASSCHGCKAFFRRSVFEGRVYM-CSADNHCDITNESRNRCRACRLRNCLEGGMNPKHVR 218
Cdd:cd07158   1 CKVCG-DKASGFHYGVHSCEGCKGFFRRTIQHNLTYRrCLNGGKCVIQRKNRNRCQYCRFKKCLSVGMSRNAVR 73

The DNA binding domain of GR_like nuclear receptors is composed of two C4-type zinc fingers; The DNA binding domain of GR_like nuclear receptors is composed of two C4-type zinc fingers. Each zinc finger contains a group of four Cys residues which co-ordinates a single zinc atom. It interacts with specific DNA sites upstream of the target gene and modulates the rate of transcriptional initiation. This family of NRs includes four types of nuclear hormone receptors: glucocorticoid receptor (GR), mineralocorticoid receptor (MR), progesterone receptor (PR), and androgen receptor (AR). The receptors bind to common DNA elements containing a partial palindrome of the core sequence 5'-TGTTCT-3' with a 3bp spacer. These four receptors regulate some of the most fundamental physiological functions such as the stress response, metabolism, electrolyte homeostasis, immune function, growth, development, and reproduction. The NRs in this family have high sequence homology and share similar functional mechanisms. The dominant mechanism of function is by direct DNA binding and transcriptional regulation of target genes . The GR, MR, PR, and AR exhibit same modular structure. They have a central highly conserved DNA binding domain (DBD), a non-conserved N-terminal domain, a flexible hinge and a C-terminal ligand binding domain (LBD).

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 71984640 146 CVGCGSESAiRVHYGASSCHGCKAFFRRSVFEGRVYMCSADNHCDITNESRNRCRACRLRNCLEGGMN 213
Cdd:cd06963   1 CLICGDEAS-GCHYGVLTCGSCKVFFKRAAEGQHNYLCAGRNDCIIDKIRRKNCPACRLRKCYQAGMT 67

DNA-binding domain of androgen receptor (AR) is composed of two C4-type zinc fingers; DNA-binding domain of androgen receptor (AR) is composed of two C4-type zinc fingers. Each zinc finger contains a group of four Cys residues which co-ordinates a single zinc atom. To regulate gene expression, AR interacts with a palindrome of the core sequence 5'-TGTTCT-3' with a 3-bp spacer. It also binds to the direct repeat 5'-TGTTCT-3' hexamer in some androgen controlled genes. AR is activated by the androgenic hormones, testosterone or dihydrotestosterone, which are responsible for primary and for secondary male characteristics, respectively. The primary mechanism of action of ARs is by direct regulation of gene transcription. The binding of androgen results in a conformational change in the androgen receptor which causes its transport from the cytosol into the cell nucleus, and dimerization. The receptor dimer binds to a hormone response element of AR regulated genes and modulates their expression. Another mode of action of androgen receptor is independent of their interactions with DNA. The receptor interacts directly with signal transduction proteins in the cytoplasm, causing rapid changes in cell function, such as ion transport. Like other members of the nuclear receptor (NR) superfamily of ligand-activated transcription factors, AR has a central well conserved DNA binding domain (DBD), a variable N-terminal domain, a flexible hinge and a C-terminal ligand binding domain (LBD).

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 71984640 146 CVGCGSEsAIRVHYGASSCHGCKAFFRRSVFEGRVYMCSADNHCDITNESRNRCRACRLRNCLEGGM 212
Cdd:cd07173   6 CLICGDE-ASGCHYGALTCGSCKVFFKRAAEGKQKYLCASRNDCTIDKFRRKNCPSCRLRKCFEAGM 71

DNA-binding domain of pregnane X receptor (PXRs) is composed of two C4-type zinc fingers; DNA-binding domain (DBD)of pregnane X receptor (PXR) is composed of two C4-type zinc fingers. Each zinc finger contains a group of four Cys residues which co-ordinates a single zinc atom. PXR DBD interacts with the PXR response element, a perfect repeat of two AGTTCA motifs with a 4 bp spacer upstream of the target gene, and modulates the rate of transcriptional initiation. The pregnane X receptor (PXR) is a ligand-regulated transcription factor that responds to a diverse array of chemically distinct ligands, including many endogenous compounds and clinical drugs. PXR functions as a heterodimer with retinoic X receptor-alpha (RXRa) and binds to a variety of promoter regions of a diverse set of target genes involved in the metabolism, transport, and ultimately, elimination of these molecules from the body. Like other nuclear receptors, PXR has a central well conserved DNA-binding domain, a variable N-terminal domain, a flexible hinge and a C-terminal ligand binding domain.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71984640 146 CVGCGsESAIRVHYGASSCHGCKAFFRRSVFEGRVYMCSADNHCDITNESRNRCRACRLRNCLEGG------MNPKHVRE 219
Cdd:cd07162   2 CRVCG-DRATGYHFNAMTCEGCKGFFRRAMKRNARLCCPFQKGCVITKSNRRQCQACRLRKCLSIGmkkeliMSDEAVEK 80

                ....*..
gi 71984640 220 ERSKIER 226
Cdd:cd07162  81 RRALIKR 87

Ligand-binding domain of nuclear receptor family 2; Ligand-binding domain (LBD) of nuclear receptor (NR) family 2: This is one of the major subfamily of nuclear receptors, including some well known nuclear receptors such as glucocorticoid receptor (GR), mineralocorticoid receptor (MR), estrogen receptor (ER), progesterone receptor (PR), and androgen receptor (AR), other related receptors. Nuclear receptors form a superfamily of ligand-activated transcription regulators, which regulate various physiological functions, from development, reproduction, to homeostasis and metabolism in animals (metazoans). The family contains not only receptors for known ligands but also orphan receptors for which ligands do not exist or have not been identified. NRs share a common structural organization with a central well conserved DNA binding domain (DBD), a variable N-terminal domain, a non-conserved hinge and a C-terminal ligand binding domain (LBD).

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71984640 379 DWAMGIPEFRVLPLADQTTLFkQN----FMAFGWITFAYKcFELKQHLTgmpLGNGAYIPYNDEDQKKLPErwaqtygvV 454
Cdd:cd06930  17 DWAKNLPAFRNLPLDDQLTLL-QNswaeLLLLGLAQRSVH-FELSELLL---PSPLLVILTEREALLGLAE--------L 83

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71984640 455 CRKLIDLIVKaMIELQITEEEYCLIKTISLFQQDC-ILSEAGQgiCSRMRDRLLDALSAHIEKRYPyhttsQRMTRALKI 533
Cdd:cd06930  84 VQRLQELLSK-LRSLQLDPKEYACLKAIVLFNPDLpGLKNQQQ--VEELQEKAQQALQEYIRKRYP-----QQPARFAKL 155

                       170
                ....*....|
gi 71984640 534 SLMLPSFSHI 543
Cdd:cd06930 156 LLRLPELRSI 165

The ligand binding domain of estrogen receptor-related nuclear receptors; The ligand binding domain of estrogen receptor-related receptors (ERRs): The family of estrogen receptor-related receptors (ERRs), a subfamily of nuclear receptors, is closely related to the estrogen receptor (ER) family, but it lacks the ability to bind estrogen. ERRs can interfere with the classic ER-mediated estrogen signaling pathway, positively or negatively. ERRs share target genes, co-regulators and promoters with the estrogen receptor (ER) family. There are three subtypes of ERRs: alpha, beta and gamma. ERRs bind at least two types of DNA sequence, the estrogen response element and another site, originally characterized as SF-1 (steroidogenic factor 1) response element. Like other members of the nuclear receptor (NR) superfamily of ligand-activated transcription factors, ERR has a central well conserved DNA binding domain (DBD), a variable N-terminal domain, a flexible hinge and a C-terminal ligand binding domain (LBD).

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71984640 365 DLYlswYRSFVFAADWAMGIPEFRVLPLADQTTLFKQNFMAFGWITFAYKCfelkqhltgmplgngayIPYNDE----DQ 440
Cdd:cd06946  34 DLA---DRELVVIIGWAKHIPGFSSLSLNDQMSLLQSAWMEILTLGVVFRS-----------------LPFNGElvfaED 93

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71984640 441 KKLPERWAQTYGVV-----CRKLidliVKAMIELQITEEEYCLIKTISLFQQDCILSEAGQGIcSRMRDRLLDALSAHIE 515
Cdd:cd06946  94 FILDEELAREAGLLelysaCLQL----VRRLQRLRLEKEEYVLLKALALANSDSVHIEDVEAV-RQLRDALLEALSDYEA 168

                       170       180
                ....*....|....*....|....*...
gi 71984640 516 KRYPyHTTSQRMTRALkisLMLPSFSHI 543
Cdd:cd06946 169 GRHP-GEAPRRAGQLL---LTLPLLRQT 192

The ligand binding domain of heptocyte nuclear factor 4, which is explosively expanded in nematodes; The ligand binding domain of hepatocyte nuclear factor 4 (HNF4) like proteins: HNF4 is a member of the nuclear receptor superfamily. HNF4 plays a key role in establishing and maintenance of hepatocyte differentiation in the liver. It is also expressed in gut, kidney, and pancreatic beta cells. HNF4 was originally classified as an orphan receptor, but later it is found that HNF4 binds with very high affinity to a variety of fatty acids. However, unlike other nuclear receptors, the ligands do not act as a molecular switch for HNF4. They seem to constantly bind to the receptor, which is constitutively active as a transcription activator. Like other members of the nuclear receptor (NR) superfamily of ligand-activated transcription factors, HNF4 has a central well conserved DNA binding domain (DBD), a variable N-terminal domain, a flexible hinge and a C-terminal ligand binding domain (LBD). The LBD domain is also responsible for recruiting co-activator proteins. More than 280 nuclear receptors are found in C. ele gans, most of which are originated from an explosive burst of duplications of HNF4.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71984640 379 DWAMGIPEFRVLPLADQTTLFKqnfmafgwitfAYKCfelkQHLT------GMP------LGNGAYIPYNDEDQkklper 446
Cdd:cd06931  50 EWAKYIPAFCELPLDDQVALLR-----------AHAG----EHLLlgvarrSMPykdillLGNDLIIPRHCPEP------ 108

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71984640 447 waQTYGVVCRkLIDLIVKAMIELQITEEEYCLIKTISLFQQDCI-LSEAGQgiCSRMRDRLLDALSAHIEKRYPyhtTSQ 525
Cdd:cd06931 109 --EISRVANR-ILDELVLPLRDLNIDDNEYACLKAIVFFDPDAKgLSDPQK--IKRLRFQVQVSLEDYINDRQY---DSR 180

                       170
                ....*....|....*...
gi 71984640 526 RmtRALKISLMLPSFSHI 543
Cdd:cd06931 181 G--RFGELLLLLPTLQSI 196

The ligand binding domain of the orphan nuclear receptors TR4 and TR2; The ligand binding domain of the TR4 and TR2 (human testicular receptor 4 and 2): TR4 and TR2 are orphan nuclear receptors. Several isoforms of TR4 and TR2 have been isolated in various tissues. TR2 is abundantly expressed in the androgen-sensitive prostate. TR4 transcripts are expressed in many tissues, including central nervous system, adrenal gland, spleen, thyroid gland, and prostate. The expression of TR2 is negatively regulated by androgen, retinoids, and radiation. The expression of both mouse TR2 and TR4 is up-regulated by neurocytokine ciliary neurotrophic factor (CNTF) in mouse. It has shown that human TR2 binds to a wide spectrum of natural hormone response elements (HREs) with distinct affinities suggesting that TR2 may cross-talk with other gene expression regulation systems. The genes responding to TR2 or TR4 include genes that are regulated by retinoic acid receptor, vitamin D receptor, peroxisome proliferator-activated receptor. TR4/2 binds to HREs as a dimer. Like other members of the nuclea r receptor (NR) superfamily of ligand-activated transcription factors, TR2-like receptors have a central well conserved DNA binding domain (DBD), a variable N-terminal domain, a flexible hinge and a C-terminal ligand binding domain (LBD).

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71984640 334 DITLTFGLQHPQMVIKRLPLKYSCdrimEAAD--LYLSwyrsfvfaADWAMGIPEFRVLPLADQTTLFKQ---NFMAFGw 408
Cdd:cd06952   4 DVHVAFKLQMPSPMPSYLNVHYIC----ESASrlLFLS--------IHWARSIPAFQALGAETQTSLVRAcwpELFTLG- 70

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71984640 409 itfaykcfeLKQHLTGMPLGN--GAYIPY--NDEDQKKLPerwaqtyGVVCRKLIDLIVK------AMIELQITEEEYCL 478
Cdd:cd06952  71 ---------LAQCSQQLSLPTilAAIINHlqTSIQQDKLS-------ADKVKQVMEHINKlqefvnSMQKLDVDDHEYAY 134

                       170       180       190       200       210       220
                ....*....|....*....|....*....|....*....|....*....|....*....|
gi 71984640 479 IKTISLFQQDCILSEAGQGIcSRMRDRLLDALSAHIEKRYPYHTtsQRMTRALkisLMLP 538
Cdd:cd06952 135 LKAIVLFSPDHPGQELRQQI-EKLQEKALMELRDYVGKTYPEDE--YRLSKLL---LRLP 188