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 453232620  189 KMEKVGELPVRQLFVIFEKQMVMIAEWLIHNPDFRMLDEEEKYLYFKAVWNMWRRFERFEMSVKMFGNQKFAISNEKL-- 266
Cdd:pfam00104   4 PLKKLRKATKEELCELWERDLLLVAEWAKHFPEFQELPLEDQMALLKSFWLEWLRLEKAARSAKLRRKKILGEDVLMIsd 83

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 453232620  267 -MVMDSCIDYSEITDLPNSKVAEMFRLTRSKLFHQLAKPLMELNPSSIEMAYMLTQLSWQIAGKKMQGNVIEIGERVCDN 345
Cdd:pfam00104  84 dDAMKFVEDDSSWCTNYDLEQLLFFLPFFNSYFFELVKPLRELNPDDEELAYLLAQLLFDYAGDGLSGEILEIVEKLQEK 163

                         170       180       190
                  ....*....|....*....|....*....|....*.
gi 453232620  346 LADDLHSYYQKnekrsNYAGRLVRLMNIVNAMKKIH 381
Cdd:pfam00104 164 LANELHDYYVN-----KYSGRLAKLLKILPSLRKIS 194

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 453232620  189 KMEKVGELPVRQLFVIFEKQMVMIAEWLIHNPDFRMLDEEEKYLYFKAVWNMWRRFERFEMSVKMFGNQKFAISNEKL-- 266
Cdd:pfam00104   4 PLKKLRKATKEELCELWERDLLLVAEWAKHFPEFQELPLEDQMALLKSFWLEWLRLEKAARSAKLRRKKILGEDVLMIsd 83

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 453232620  267 -MVMDSCIDYSEITDLPNSKVAEMFRLTRSKLFHQLAKPLMELNPSSIEMAYMLTQLSWQIAGKKMQGNVIEIGERVCDN 345
Cdd:pfam00104  84 dDAMKFVEDDSSWCTNYDLEQLLFFLPFFNSYFFELVKPLRELNPDDEELAYLLAQLLFDYAGDGLSGEILEIVEKLQEK 163

                         170       180       190
                  ....*....|....*....|....*....|....*.
gi 453232620  346 LADDLHSYYQKnekrsNYAGRLVRLMNIVNAMKKIH 381
Cdd:pfam00104 164 LANELHDYYVN-----KYSGRLAKLLKILPSLRKIS 194

Ligand binding domain of hormone receptors;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 453232620   205 FEKQMVMIAEWLIHNPDFRMLDEEEKYLYFKAVWNMWRRFERFEMSVKMFGNQKFaisneklmvmdsCIDYSEITDLPNS 284
Cdd:smart00430   1 AERQLLLTVEWAKSFPGFRELSLEDQIVLLKSFWFELLLLELAYRSVKLKKELLL------------APDGTYIRPDAVL 68

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 453232620   285 KVAEMFRLTRSKLFHQLAKPLMELNPSSIEMAYMLTQLSWQIAGKKMQGNVIEIGERVCDNLADDLHSYYQKNeKRSNYA 364
Cdd:smart00430  69 ELRKLFSPFLDRILSELVKPLRELKLDDEEYALLKAIVLFNPAVPGLSEEGKEIVEKLQEKYANALHDYYLKN-YPMNYP 147

                          170
                   ....*....|....*.
gi 453232620   365 GRLVRLMNIVNAMKKI 380
Cdd:smart00430 148 GRFAKLLLILPELRKI 163

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        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 453232620   23 LCKVCALSAHGSHFGVLACRACAAFFRRTVvlERQKQYKCKKGKNeCPVDTAERYQCRLCRYNKCVDLGMT 93
Cdd:pfam00105   1 LCKVCGDKASGYHYGVLTCEGCKGFFRRSI--QKNIVYTCKFNKD-CVIDKRNRNRCQYCRLKKCLEVGMS 68

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 453232620  189 KMEKVGELPVRQLFVIFEKQMVMIAEWLIHNPDFRMLDEEEKYLYFKAVWNMWRRFERFEMSVKMFGNQKFAISNEKL-- 266
Cdd:pfam00104   4 PLKKLRKATKEELCELWERDLLLVAEWAKHFPEFQELPLEDQMALLKSFWLEWLRLEKAARSAKLRRKKILGEDVLMIsd 83

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 453232620  267 -MVMDSCIDYSEITDLPNSKVAEMFRLTRSKLFHQLAKPLMELNPSSIEMAYMLTQLSWQIAGKKMQGNVIEIGERVCDN 345
Cdd:pfam00104  84 dDAMKFVEDDSSWCTNYDLEQLLFFLPFFNSYFFELVKPLRELNPDDEELAYLLAQLLFDYAGDGLSGEILEIVEKLQEK 163

                         170       180       190
                  ....*....|....*....|....*....|....*.
gi 453232620  346 LADDLHSYYQKnekrsNYAGRLVRLMNIVNAMKKIH 381
Cdd:pfam00104 164 LANELHDYYVN-----KYSGRLAKLLKILPSLRKIS 194

Ligand binding domain of hormone receptors;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 453232620   205 FEKQMVMIAEWLIHNPDFRMLDEEEKYLYFKAVWNMWRRFERFEMSVKMFGNQKFaisneklmvmdsCIDYSEITDLPNS 284
Cdd:smart00430   1 AERQLLLTVEWAKSFPGFRELSLEDQIVLLKSFWFELLLLELAYRSVKLKKELLL------------APDGTYIRPDAVL 68

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 453232620   285 KVAEMFRLTRSKLFHQLAKPLMELNPSSIEMAYMLTQLSWQIAGKKMQGNVIEIGERVCDNLADDLHSYYQKNeKRSNYA 364
Cdd:smart00430  69 ELRKLFSPFLDRILSELVKPLRELKLDDEEYALLKAIVLFNPAVPGLSEEGKEIVEKLQEKYANALHDYYLKN-YPMNYP 147

                          170
                   ....*....|....*.
gi 453232620   365 GRLVRLMNIVNAMKKI 380
Cdd:smart00430 148 GRFAKLLLILPELRKI 163

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 453232620  24 CKVCALSAHGSHFGVLACRACAAFFRRTVvlERQKQYKCKKGKNeCPVDTAERYQCRLCRYNKCVDLGMTPENVQ 98
Cdd:cd06916    1 CAVCGDKASGYHYGVLTCEGCKGFFRRSV--RRNLEYTCPAGGN-CVIDKRNRNRCQACRLKKCLAVGMRKEAVR 72

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 453232620  24 CKVCALSAHGSHFGVLACRACAAFFRRTVvlERQKQYKCK-KGKNECPVDTAERYQCRLCRYNKCVDLGMTPENVQFNR 101
Cdd:cd07163    9 CKVCGDRSSGKHYGIYACDGCSGFFKRSI--RRNRQYVCKsKGQGGCPVDKTHRNQCRACRLKKCFEVGMNKDAVQHER 85

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        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 453232620   23 LCKVCALSAHGSHFGVLACRACAAFFRRTVvlERQKQYKCKKGKNeCPVDTAERYQCRLCRYNKCVDLGMT 93
Cdd:pfam00105   1 LCKVCGDKASGYHYGVLTCEGCKGFFRRSI--QKNIVYTCKFNKD-CVIDKRNRNRCQYCRLKKCLEVGMS 68

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 453232620  23 LCKVCALSAHGSHFGVLACRACAAFFRRTVvlerQKQ--YKCKkGKNECPVDTAERYQCRLCRYNKCVDLGMTPENVqfn 100
Cdd:cd06961    1 PCVVCGDKATGYHYRCITCEGCKGFFRRTV----QKKlsYSCK-GEGKCEIDKVTRNQCQECRFKKCIAVGMAKDLV--- 72

                         90
                 ....*....|.
gi 453232620 101 RESASRTRKRK 111
Cdd:cd06961   73 LDDRKRGAKRK 83

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        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 453232620  24 CKVCALSAHGSHFGVLACRACAAFFRRTVvlERQKQYKCKKGKNeCPVDTAERYQCRLCRYNKCVDLGMTPENVQFNRES 103
Cdd:cd07167    1 CPVCGDKVSGYHYGLLTCESCKGFFKRTV--QNKKRYTCIENQN-CQIDKTQRKRCPYCRFQKCLSVGMKLEAVRADRMR 77

                 ....*
gi 453232620 104 ASRTR 108
Cdd:cd07167   78 GGRNK 82

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 453232620  21 IVLCKVCALSAHGSHFGVLACRACAAFFRRTvvLERQKQYKCKKGKNeCPVDTAERYQCRLCRYNKCVDLGMTPENVQFN 100
Cdd:cd06968    5 VIPCKICGDKSSGIHYGVITCEGCKGFFRRS--QQNNVSYSCPRQKN-CLIDRTNRNRCQHCRLQKCLALGMSRDAVKFG 81

                 ....*....
gi 453232620 101 RESASRTRK 109
Cdd:cd06968   82 RMSKKQRDS 90

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 453232620  23 LCKVCALSAHGSHFGVLACRACAAFFRRTVvlERQKQYKCKKGKNeCPVDTAERYQCRLCRYNKCVDLGMTPENVQFNR 101
Cdd:cd06956    2 ICAICGDRASGKHYGVYSCEGCKGFFKRTV--RKDLTYTCRDNKD-CLIDKRQRNRCQYCRYQKCLAMGMKREAVQEER 77

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 453232620  23 LCKVCALSAHGSHFGVLACRACAAFFRRTVvlERQKQYKCkKGKNECPVDTAERYQCRLCRYNKCVDLGMTPENVQFNRE 102
Cdd:cd07168    8 LCSICEDKATGLHYGIITCEGCKGFFKRTV--QNKRVYTC-VGDGRCEITKAQRNRCQYCRFRKCIRKGMMLAAVREDRM 84

                 ....
gi 453232620 103 SASR 106
Cdd:cd07168   85 PGGR 88

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        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 453232620  20 TIVLCKVCALSAHGSHFGVLACRACAAFFRRTVvlERQKQYK-CKKGKNeCPVDTAERYQCRLCRYNKCVDLGMTPENVQ 98
Cdd:cd07166    2 MVVLCKVCGDKASGFHYGVHACEGCKGFFRRSI--QQKIQYRkCTKNET-CSIMRINRNRCQYCRFKKCLAVGMSRDAVR 78

                 ...
gi 453232620  99 FNR 101
Cdd:cd07166   79 FGR 81

DNA-binding domain of estrogen related receptors (ERR) is composed of two C4-type zinc fingers; DNA-binding domain of estrogen related receptors (ERRs) is composed of two C4-type zinc fingers. Each zinc finger contains a group of four Cys residues which coordinates a single zinc atom. ERR interacts with the palindromic inverted repeat, 5'GGTCAnnnTGACC-3', upstream of the target gene and modulates the rate of transcriptional initiation. The estrogen receptor-related receptors (ERRs) are transcriptional regulators, which are closely related to the estrogen receptor (ER) family. Although ERRs lack the ability to bind to estrogen and are so-called orphan receptors, they share target genes, co-regulators and promoters with the estrogen receptor (ER) family. By targeting the same set of genes, ERRs seem to interfere with the classic ER-mediated estrogen response in various ways. 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 non-conserved hinge and a C-terminal ligand binding domain (LBD).

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 453232620  23 LCKVCALSAHGSHFGVLACRACAAFFRRTVvlERQKQYKCkKGKNECPVDTAERYQCRLCRYNKCVDLGMTPENVQFNRE 102
Cdd:cd07170    6 LCLVCGDIASGYHYGVASCEACKAFFKRTI--QGNIEYSC-PATNECEITKRRRKSCQACRFMKCLKVGMLKEGVRLDRV 82

                         90
                 ....*....|...
gi 453232620 103 SASRTRKRKNENS 115
Cdd:cd07170   83 RGGRQKYKRRIDA 95

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 453232620  20 TIVLCKVCALSAHGSHFGVLACRACAAFFRRTVvlERQKQYKCKkGKNECPVDTAERYQCRLCRYNKCVDLGMTPENVQF 99
Cdd:cd06967    2 PVELCVVCGDKASGRHYGAVSCEGCKGFFKRSI--RKNLGYSCR-GSKDCVINKHHRNRCQYCRLQKCLAMGMKSDSVQC 78

                 ..
gi 453232620 100 NR 101
Cdd:cd06967   79 ER 80

DNA-binding domain of retinoic acid receptor (RAR) is composed of two C4-type zinc fingers; DNA-binding domain of retinoic acid receptor (RAR) 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. RAR interacts with specific DNA sites upstream of the target gene and modulates the rate of transcriptional initiation. RARs mediate the biological effect of retinoids, including both natural dietary vitamin A (retinol) metabolites and active synthetic analogs. Retinoids play key roles in a wide variety of essential biological processes, such as vertebrate embryonic morphogenesis and organogenesis, differentiation and apoptosis, and homeostasis. RAR function as a heterodimer with retinoic X receptor by binding to specific RAR response elements (RAREs), which are composed of two direct repeats of the consensus sequence 5'-AGGTCA-3' separated by one to five base pair and found in the promoter regions of retinoid target genes. Like other members of the nuclear receptor (NR) superfamily of ligand-activated transcription factors, retinoic acid 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 453232620  18 PATIVLCKVCALSAHGSHFGVLACRACAAFFRRTVvlERQKQYKCKKGKNeCPVDTAERYQCRLCRYNKCVDLGMTPENV 97
Cdd:cd06964    1 PRIYKPCFVCQDKSSGYHYGVSACEGCKGFFRRSI--QKNMVYTCHRDKN-CIINKVTRNRCQYCRLQKCFEVGMSKESV 77

                 ....*
gi 453232620  98 QFNRE 102
Cdd:cd06964   78 RNDRN 82

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        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 453232620  24 CKVCALSAHGSHFGVLACRACAAFFRRTVvlERQKQYKCKKGkNECPVDTAERYQCRLCRYNKCVDLGMTPE 95
Cdd:cd07156    1 CGVCGDRATGYHFNAMTCEGCKGFFRRSM--KRKARFTCPFN-GDCEITKDNRRHCQACRLKKCLDIGMKKE 69

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        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 453232620  23 LCKVCALSAHGSHFGVLACRACAAFFRRTVvlerQKQYKCKKGKNECPVDTAERYQCRLCRYNKCVDLGMTPENVQFNR 101
Cdd:cd06965    1 ECRVCGDKASGFHYGVHACEGCKGFFRRTI----RLKLVYKPCDLSCKIHKKSRNKCQYCRFQKCLNVGMSHNAIRFGR 75

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        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 453232620  24 CKVCALSAHGSHFGVLACRACAAFFRRTVvlERQKQYKCkKGKNECPVDTAERYQCRLCRYNKCVDLGMTPENVQF 99
Cdd:cd06963    1 CLICGDEASGCHYGVLTCGSCKVFFKRAA--EGQHNYLC-AGRNDCIIDKIRRKNCPACRLRKCYQAGMTLGARKL 73

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 453232620  24 CKVCALSAHGSHFGVLACRACAAFFRRTVvlERQKQYK-CKKGKNeCPVDTAERYQCRLCRYNKCVDLGMTPENVQ 98
Cdd:cd07158    1 CKVCGDKASGFHYGVHSCEGCKGFFRRTI--QHNLTYRrCLNGGK-CVIQRKNRNRCQYCRFKKCLSVGMSRNAVR 73

DNA-binding domain of vitamin D receptors (VDR) is composed of two C4-type zinc fingers; DNA-binding domain of vitamin D receptors (VDR) is composed of two C4-type zinc fingers. Each zinc finger contains a group of four Cys residues which coordinates a single zinc atom. VDR interacts with a VDR response element, a direct repeat of GGTTCA DNA site with 3 bp spacer upstream of the target gene, and modulates the rate of transcriptional initiation. VDR is a member of the nuclear receptor (NR) superfamily that functions as classical endocrine receptors. VDR controls a wide range of biological activities including calcium metabolism, cell proliferation and differentiation, and immunomodulation. VDR is a high-affinity receptor for the biologically most active Vitamin D metabolite, 1alpha,25-dihydroxyvitamin D3 (1alpha,25(OH)2D3). The binding of the ligand to the receptor induces a conformational change of the ligand binding domain (LBD) with consequent dissociation of corepressors. Upon ligand binding, VDR forms a heterodimer with the retinoid X receptor (RXR) that binds to vitamin D response elements (VDREs), recruits coactivators. This leads to the expression of a large number of genes. Approximately 200 human genes are considered to be primary targets of VDR and even more genes are regulated indirectly. Like other members of the nuclear receptor (NR) superfamily of ligand-activated transcription factors, VDR 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 453232620  23 LCKVCALSAHGSHFGVLACRACAAFFRRTvvLERQKQYKCKKgKNECPVDTAERYQCRLCRYNKCVDLGM------TPEN 96
Cdd:cd06955    8 ICGVCGDRATGFHFNAMTCEGCKGFFRRS--MKRKALFTCPF-NGDCRITKDNRRHCQACRLKRCVDIGMmkefilTDEE 84

                         90       100
                 ....*....|....*....|...
gi 453232620  97 VQFNRESasrTRKRKNENSIAQT 119
Cdd:cd06955   85 VQRKREM---ILKRKEEEALKES 104

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 453232620 204 IFEKQMVMIAEWLIHNPDFRMLDEEEKYLYFKAVWNMWRRFERFEMSVKMFGNQkfaisneklmvmdscIDYSEITDLPN 283
Cdd:cd06157    6 LATRDLLLIVEWAKSIPGFRELPLEDQIVLLKSFWLELLVLDLAYRSYKNGLSL---------------LLAPNGGHTDD 70

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 453232620 284 SKVAEMFRLTRS---KLFHQLAKPLMELNPSSIEMAYMLTQLSWQIAGKKMQGNViEIGERVCDNLADDLHSYYQKNeKR 360
Cdd:cd06157   71 DKEDEMKLLLKGeliRLLFEFVNPLRALKLDDEEYALLKAIVLFSPDRKESLEDR-KIVEELQERLLEALQDYLRKN-YP 148

                        170       180
                 ....*....|....*....|
gi 453232620 361 SNYAGRLVRLMNIVNAMKKI 380
Cdd:cd06157  149 EEAPSRFAKLLLLLPSLRKL 168