The ligand binding domain of nuclear receptors, a family of ligand-activated transcription regulators; Ligand-binding domain (LBD) of nuclear receptor (NR): Nuclear receptors form a superfamily of ligand-activated transcription regulators, which regulate various physiological functions in metazoans, from development, reproduction, to homeostasis and metabolism. The superfamily contains not only receptors for known ligands but also orphan receptors for which ligands do not exist or have not been identified. The members of the family include receptors of steroids, thyroid hormone, retinoids, cholesterol by-products, lipids and heme. With few exceptions, 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 1831515974 187 EACAQSIREVSLVADWVAWCFDDFVTLPMDQKKVLFRNFYTPFSVLEGAFLCHINDTSNALILPSGDYIDtnnlksffni 266
Cdd:cd06157     1 ELLCELATRDLLLIVEWAKSIPGFRELPLEDQIVLLKSFWLELLVLDLAYRSYKNGLSLLLAPNGGHTDD---------- 70

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1831515974 267 pdeeqpMTDDEIEKMFKPSFELNRRGLVLPMMAEKIDVFEFFALCTFVFWDFGLDEqTDDCMMIGKSVKDRVMKELAFYL 346
Cdd:cd06157    71 ------DKEDEMKLLLKGELIRLLFEFVNPLRALKLDDEEYALLKAIVLFSPDRKE-SLEDRKIVEELQERLLEALQDYL 143

                         170       180
                  ....*....|....*....|....*.
gi 1831515974 347 RCAKRLEEPSlRVASLLTLLPALQRC 372
Cdd:cd06157   144 RKNYPEEAPS-RFAKLLLLLPSLRKL 168

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 1831515974  24 CSICREDGDGYHFGAEACRACAAFFRRSVSLDKTYLCRGNNDCEITANIRCMCRSCRFAKCLEVGMNPAGVQQRRD 99
Cdd:cd06960     1 CAVCGDRATGKHYGVLSCNGCKGFFRRSVRKNRTYTCRFGGNCVVDKDKRNACRYCRFKKCLEVGMDPEAVQNERD 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 1831515974 178 KTPKAVNYKEACAQSIREVSLVADWvAWCFDDFVTLPMDQKKVLFRNFYTPFSVLEGAFLCHINDTSNaLILPSGDYIDT 257
Cdd:pfam00104   6 KKLRKATKEELCELWERDLLLVAEW-AKHFPEFQELPLEDQMALLKSFWLEWLRLEKAARSAKLRRKK-ILGEDVLMISD 83

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1831515974 258 NNLKSFFNIPDEEQPMTDDEIEKMFKPSFELNRRGLVLPMMAEKIDVFEFFALCTFVFWDFGLDEQTDDCMMIGKSVKDR 337
Cdd:pfam00104  84 DDAMKFVEDDSSWCTNYDLEQLLFFLPFFNSYFFELVKPLRELNPDDEELAYLLAQLLFDYAGDGLSGEILEIVEKLQEK 163

                         170       180       190
                  ....*....|....*....|....*....|....
gi 1831515974 338 VMKELAFYLRcakrlEEPSLRVASLLTLLPALQR 371
Cdd:pfam00104 164 LANELHDYYV-----NKYSGRLAKLLKILPSLRK 192

Ligand binding domain of hormone receptors;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1831515974  194 REVSLVADWvAWCFDDFVTLPMDQKKVLFRNFYTPFSVLEGAFLChINDTSNALILPSGDYIDtnnlksffnipdeeqPM 273
Cdd:smart00430   3 RQLLLTVEW-AKSFPGFRELSLEDQIVLLKSFWFELLLLELAYRS-VKLKKELLLAPDGTYIR---------------PD 65

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1831515974  274 TDDEIEKMFKPSFELNRRGLVLPMMAEKIDVFEFFALCTFVFWDFGLDEQTDDCMMIGKSVKDRVMKELAFYLRCaKRLE 353
Cdd:smart00430  66 AVLELRKLFSPFLDRILSELVKPLRELKLDDEEYALLKAIVLFNPAVPGLSEEGKEIVEKLQEKYANALHDYYLK-NYPM 144

                          170
                   ....*....|....*...
gi 1831515974  354 EPSLRVASLLTLLPALQR 371
Cdd:smart00430 145 NYPGRFAKLLLILPELRK 162

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 1831515974  24 CSICREDGDGYHFGAEACRACAAFFRRSVSLDKTYLCRGNNDCEITANIRCMCRSCRFAKCLEVGMNPAGVQQRRD 99
Cdd:cd06960     1 CAVCGDRATGKHYGVLSCNGCKGFFRRSVRKNRTYTCRFGGNCVVDKDKRNACRYCRFKKCLEVGMDPEAVQNERD 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 1831515974 178 KTPKAVNYKEACAQSIREVSLVADWvAWCFDDFVTLPMDQKKVLFRNFYTPFSVLEGAFLCHINDTSNaLILPSGDYIDT 257
Cdd:pfam00104   6 KKLRKATKEELCELWERDLLLVAEW-AKHFPEFQELPLEDQMALLKSFWLEWLRLEKAARSAKLRRKK-ILGEDVLMISD 83

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1831515974 258 NNLKSFFNIPDEEQPMTDDEIEKMFKPSFELNRRGLVLPMMAEKIDVFEFFALCTFVFWDFGLDEQTDDCMMIGKSVKDR 337
Cdd:pfam00104  84 DDAMKFVEDDSSWCTNYDLEQLLFFLPFFNSYFFELVKPLRELNPDDEELAYLLAQLLFDYAGDGLSGEILEIVEKLQEK 163

                         170       180       190
                  ....*....|....*....|....*....|....
gi 1831515974 338 VMKELAFYLRcakrlEEPSLRVASLLTLLPALQR 371
Cdd:pfam00104 164 LANELHDYYV-----NKYSGRLAKLLKILPSLRK 192

Zinc finger, C4 type (two domains); In nearly all cases, this is the DNA binding domain of a nuclear hormone receptor. The alignment contains two Zinc finger domains that are too dissimilar to be aligned with each other.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1831515974  23 TCSICREDGDGYHFGAEACRACAAFFRRSVSLDKTYLCRGNNDCEITANIRCMCRSCRFAKCLEVGMN 90
Cdd:pfam00105   1 LCKVCGDKASGYHYGVLTCEGCKGFFRRSIQKNIVYTCKFNKDCVIDKRNRNRCQYCRLKKCLEVGMS 68

DNA-binding domain of ecdysone-induced DHR4 orphan nuclear receptor is composed of two C4-type zinc fingers; DNA-binding domain of ecdysone-induced DHR4 orphan nuclear receptor 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. Ecdysone-induced orphan receptor DHR4 is a member of the nuclear receptor family. DHR4 is expressed during the early Drosophila larval development and is induced by ecdysone. DHR4 coordinates growth and maturation in Drosophila by mediating endocrine response to the attainment of proper body size during larval development. Mutations in DHR4 result in shorter larval development which translates into smaller and lighter flies. Like other members of the nuclear receptor (NR) superfamily of ligand-activated transcription factors, DHR4 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 1831515974  17 EKKEKSTCSICREDGDGYHFGAEACRACAAFFRRSVSLDKTYLCRGNNDCEITANIRCMCRSCRFAKCLEVGMNPAGVQQ 96
Cdd:cd07168     2 EDESPKLCSICEDKATGLHYGIITCEGCKGFFKRTVQNKRVYTCVGDGRCEITKAQRNRCQYCRFRKCIRKGMMLAAVRE 81

                  ..
gi 1831515974  97 RR 98
Cdd:cd07168    82 DR 83

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 1831515974  24 CSICREDGDGYHFGAEACRACAAFFRRSVSLDKTYLCRGNNDCEITANIRCMCRSCRFAKCLEVGMNPAGVQQRRDTIGK 103
Cdd:cd06961     2 CVVCGDKATGYHYRCITCEGCKGFFRRTVQKKLSYSCKGEGKCEIDKVTRNQCQECRFKKCIAVGMAKDLVLDDRKRGAK 81

                  ....
gi 1831515974 104 REIK 107
Cdd:cd06961    82 RKLI 85

Ligand binding domain of hormone receptors;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1831515974  194 REVSLVADWvAWCFDDFVTLPMDQKKVLFRNFYTPFSVLEGAFLChINDTSNALILPSGDYIDtnnlksffnipdeeqPM 273
Cdd:smart00430   3 RQLLLTVEW-AKSFPGFRELSLEDQIVLLKSFWFELLLLELAYRS-VKLKKELLLAPDGTYIR---------------PD 65

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1831515974  274 TDDEIEKMFKPSFELNRRGLVLPMMAEKIDVFEFFALCTFVFWDFGLDEQTDDCMMIGKSVKDRVMKELAFYLRCaKRLE 353
Cdd:smart00430  66 AVLELRKLFSPFLDRILSELVKPLRELKLDDEEYALLKAIVLFNPAVPGLSEEGKEIVEKLQEKYANALHDYYLK-NYPM 144

                          170
                   ....*....|....*...
gi 1831515974  354 EPSLRVASLLTLLPALQR 371
Cdd:smart00430 145 NYPGRFAKLLLILPELRK 162

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 1831515974  24 CSICREDGDGYHFGAEACRACAAFFRRSVSLDKTYLCRGNNDCEITANIRCMCRSCRFAKCLEVGMNPAGVQQRRDTIGK 103
Cdd:cd06967     6 CVVCGDKASGRHYGAVSCEGCKGFFKRSIRKNLGYSCRGSKDCVINKHHRNRCQYCRLQKCLAMGMKSDSVQCERKPIDV 85

                  .
gi 1831515974 104 R 104
Cdd:cd06967    86 S 86

DNA-binding domain of Tailless (TLX) is composed of two C4-type zinc fingers; DNA-binding domain of Tailless (TLX) 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. TLX interacts with specific DNA sites upstream of the target gene and modulates the rate of transcriptional initiation. TLX is an orphan receptor that is expressed by neural stem/progenitor cells in the adult brain of the subventricular zone (SVZ) and the dentate gyrus (DG). It plays a key role in neural development by promoting cell cycle progression and preventing apoptosis in the developing brain. Like other members of the nuclear receptor (NR) superfamily of ligand-activated transcription factors, TLX 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 1831515974  24 CSICREDGDGYHFGAEACRACAAFFRRSVSLDKTYLCR--GNNDCEITANIRCMCRSCRFAKCLEVGMNPAGVQQRR 98
Cdd:cd07163     9 CKVCGDRSSGKHYGIYACDGCSGFFKRSIRRNRQYVCKskGQGGCPVDKTHRNQCRACRLKKCFEVGMNKDAVQHER 85

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 1831515974  24 CSICREDGDGYHFGAEACRACAAFFRRSVSLDKTYLCR-GNNDCEITANIRCMCRSCRFAKCLEVGMNPAGVQ 95
Cdd:cd07154     1 CKVCGDRSSGKHYGVYACDGCSGFFKRSIRRNLLYTCKaGNGSCVVDKARRNQCQACRLKKCLEVSMNKDAVQ 73

DNA-binding domain of retinoid X receptor (RXR) is composed of two C4-type zinc fingers; DNA-binding domain of retinoid X receptor (RXR) 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. RXR functions as a DNA binding partner by forming heterodimers with other nuclear receptors including CAR, FXR, LXR, PPAR, PXR, RAR, TR, and VDR. All RXR heterodimers preferentially bind response elements composed of direct repeats of two AGGTCA sites with a 1-5 bp spacer. RXRs can play different roles in these heterodimers. RXR acts either as a structural component of the heterodimer complex, required for DNA binding but not acting as a receptor, or as both a structural and a functional component of the heterodimer, allowing 9-cis RA to signal through the corresponding heterodimer. In addition, RXR can also form homodimers, functioning as a receptor for 9-cis RA, independently of other nuclear receptors. Like other members of the nuclear receptor (NR) superfamily of ligand-activated transcription factors, RXR 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 1831515974  24 CSICREDGDGYHFGAEACRACAAFFRRSVSLDKTYLCRGNNDCEITANIRCMCRSCRFAKCLEVGMNPAGVQQRR 98
Cdd:cd06956     3 CAICGDRASGKHYGVYSCEGCKGFFKRTVRKDLTYTCRDNKDCLIDKRQRNRCQYCRYQKCLAMGMKREAVQEER 77

DNA-binding domain of Ecdysone receptor (ECR) family is composed of two C4-type zinc fingers; DNA-binding domain of Ecdysone receptor (EcR) 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. EcR interacts with highly degenerate pseudo-palindromic response elements, resembling inverted repeats of 5'-AGGTCA-3' separated by 1 bp, upstream of the target gene and modulates the rate of transcriptional initiation. EcR is present only in invertebrates and regulates the expression of a large number of genes during development and reproduction. EcR functions as a heterodimer by partnering with ultraspiracle protein (USP), the ortholog of the vertebrate retinoid X receptor (RXR). The natural ligands of EcR are ecdysteroids, the endogenous steroidal hormones found in invertebrates. Like other members of the nuclear receptor (NR) superfamily of ligand-activated transcription factors, EcRs 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 1831515974  24 CSICREDGDGYHFGAEACRACAAFFRRSVSLDKTYLCRGNNDCEITANIRCMCRSCRFAKCLEVGMNPAGVQQRRDTIGK 103
Cdd:cd07161     4 CLVCGDRASGYHYNALTCEGCKGFFRRSVTKSAVYHCKYGRACEMDMYMRRKCQECRLKKCLSVGMRPECVVPESQCAIK 83

                  ....
gi 1831515974 104 REIK 107
Cdd:cd07161    84 RREK 87

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        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1831515974  24 CSICREDGDGYHFGAEACRACAAFFRRSVSLDKTYLCRGNNDCEITANIRCMCRSCRFAKCLEVGMNPAGVQQRR 98
Cdd:cd07167     1 CPVCGDKVSGYHYGLLTCESCKGFFKRTVQNKKRYTCIENQNCQIDKTQRKRCPYCRFQKCLSVGMKLEAVRADR 75

DNA-binding domain of constitutive androstane receptor (CAR) is composed of two C4-type zinc fingers; DNA-binding domain (DBD) of constitutive androstane receptor (CAR) 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. CAR DBD interacts with CAR 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 constitutive androstane receptor (CAR) is a ligand-regulated transcription factor that responds to a diverse array of chemically distinct ligands, including many endogenous compounds and clinical drugs. It functions as a heterodimer with RXR. The CAR/RXR heterodimer binds many common response elements in the promoter regions of a diverse set of target genes involved in the metabolism, transport, and ultimately, elimination of these molecules from the body. CAR is a closest mammalian relative of PXR and is activated by some of the same ligands as PXR and regulates a subset of common genes. The sequence homology and functional similarity suggests that the CAR gene arose from a duplication of an ancestral PXR gene. Like other nuclear receptors, CAR 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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1831515974  23 TCSICREDGDGYHFGAEACRACAAFFRRSVSLDKTYLCRGNNDCEITANIRCMCRSCRFAKCLEVGMN 90
Cdd:cd06966     2 ICGVCGDKALGYNFNAITCESCKAFFRRNALKNKEFKCPFNESCEINVVTRRFCQKCRLDKCFAIGMK 69

The DNA-binding domain of Ecdysone receptor (EcR) like nuclear receptor family is composed of two C4-type zinc fingers; The DNA-binding domain of Ecdysone receptor (EcR) 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. EcR interacts with specific DNA sites upstream of the target gene and modulates the rate of transcriptional initiation. This family includes three types of nuclear receptors: Ecdysone receptor (EcR), Liver X receptor (LXR) and Farnesoid X receptor (FXR). The DNA binding activity is regulated by their corresponding ligands. The ligands for EcR are ecdysteroids; LXR is regulated by oxidized cholesterol derivatives or oxysterols; and bile acids control FXR's activities. Like other members of the nuclear receptor (NR) superfamily of ligand-activated transcription factors, EcR-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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1831515974  24 CSICREDGDGYHFGAEACRACAAFFRRSVSLDKTYLCRGNNDCEITANIRCMCRSCRFAKCLEVGMNP 91
Cdd:cd06959     2 CVVCGDKASGFHYGVLSCEGCKGFFRRSVTKGAVYACKFGNKCEMDMYMRRKCQECRLRKCKAAGMRP 69

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        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1831515974  20 EKSTCSICREDGDGYHFGAEACRACAAFFRRSVSLDKTYLCRGNNDCEITANIRCMCRSCRFAKCLEVGMnpagvqqrrd 99
Cdd:cd07173     2 PQKTCLICGDEASGCHYGALTCGSCKVFFKRAAEGKQKYLCASRNDCTIDKFRRKNCPSCRLRKCFEAGM---------- 71

                  ....*...
gi 1831515974 100 TIGKREIK 107
Cdd:cd07173    72 TLGARKLK 79

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 1831515974  15 RPEKKEK---------STCSICREDGDGYHFGAEACRACAAFFRRSVSLDKTYLCRGNNDCEITANIRCMCRSCRFAKCL 85
Cdd:cd07160     3 PPRKRKKgpapkmlgnEVCSVCGDKASGFHYNVLSCEGCKGFFRRSVIKGAQYVCKNGGKCQMDMYMRRKCQECRLRKCR 82

                  ....
gi 1831515974  86 EVGM 89
Cdd:cd07160    83 EAGM 86

The first DNA-binding domain (DBD) of the 2DBD nuclear receptors is composed of two C4-type zinc fingers; The first DNA-binding domain (DBD) of the 2DBD nuclear receptors(NRs) 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. Theses proteins contain two DBDs in tandem, probably resulted from an ancient recombination event. The 2DBD-NRs are found only in flatworm species, mollusks and arthropods. Their biological function is unknown.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1831515974  23 TCSICREDGDGYHFGAEACRACAAFFRRSVSLD--KTYLCRGNNDCEITANIRCMCRSCRFAKCLEVGMN--PAGVQQRR 98
Cdd:cd07157     2 TCQVCGEPAAGFHHGAYVCEACKKFFMRSSNAIsfTISECPNGGKCIIDKKNRTKCQACRYRKCLNVGMSlgGPRYGRRS 81

                  .
gi 1831515974  99 D 99
Cdd:cd07157    82 D 82

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 1831515974  24 CSICREDGDGYHFGAEACRACAAFFRRSVSLDKTYLCRGNNDCEITANIRCMCRSCRFAKCLEVG------MNPAGVQQR 97
Cdd:cd07162     2 CRVCGDRATGYHFNAMTCEGCKGFFRRAMKRNARLCCPFQKGCVITKSNRRQCQACRLRKCLSIGmkkeliMSDEAVEKR 81

                  ....
gi 1831515974  98 RDTI 101
Cdd:cd07162    82 RALI 85

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 1831515974  24 CSICREDGDGYHFGAEACRACAAFFRRSVSLDKTYLCRGNNDCEITANIRCMCRSCRFAKCLEVGMNPAGVQQRRDTIGK 103
Cdd:cd06968     8 CKICGDKSSGIHYGVITCEGCKGFFRRSQQNNVSYSCPRQKNCLIDRTNRNRCQHCRLQKCLALGMSRDAVKFGRMSKKQ 87

                  ....*...
gi 1831515974 104 REIKPDST 111
Cdd:cd06968    88 RDSLYAEV 95

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 1831515974  24 CSICREDGDGYHFGAEACRACAAFFRRSVSLDKTYL-CRGNNDCEITANIRCMCRSCRFAKCLEVGMNPAGVQ 95
Cdd:cd07158     1 CKVCGDKASGFHYGVHSCEGCKGFFRRTIQHNLTYRrCLNGGKCVIQRKNRNRCQYCRFKKCLSVGMSRNAVR 73

DNA-binding domain of peroxisome proliferator-activated receptors (PPAR) is composed of two C4-type zinc fingers; DNA-binding domain of peroxisome proliferator-activated receptors (PPAR) 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. PPAR interacts with specific DNA sites upstream of the target gene and modulates the rate of transcriptional initiation. Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily of ligand-activated transcription factors. PPARs play important roles in regulating cellular differentiation, development and lipid metabolism. Activated PPAR forms a heterodimer with the retinoid X receptor (RXR) that binds to the hormone response elements, which are composed of two direct repeats of the consensus sequence 5'-AGGTCA-3' separated by one to five base pair located upstream of the peroxisome proliferator responsive genes, and interacts with co-activators. Several essential fatty acids, oxidized lipids and prostaglandin J derivatives can bind and activate PPAR. Like other members of the nuclear receptor (NR) superfamily of ligand-activated transcription factors, PPAR has a central well conserved DNA binding domain (DBD), a variable N-terminal regulatory domain, a flexible hinge and a C-terminal ligand binding domain (LBD).

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1831515974  24 CSICREDGDGYHFGAEACRACAAFFRRSVSLDKTY-LCRGNndCEITANIRCMCRSCRFAKCLEVGM 89
Cdd:cd06965     2 CRVCGDKASGFHYGVHACEGCKGFFRRTIRLKLVYkPCDLS--CKIHKKSRNKCQYCRFQKCLNVGM 66