Ligand binding domain of hormone receptors;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 392898793   184 QKQEYVMLFNYANTLPGFQELSNASQNFLFRIACGVDYVISSSYYTLCIGTEsnLLINQDGTYIQMMPLPLMGDEPGTEL 263
Cdd:smart00430   1 AERQLLLTVEWAKSFPGFRELSLEDQIVLLKSFWFELLLLELAYRSVKLKKE--LLLAPDGTYIRPDAVLELRKLFSPFL 78

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 392898793   264 MftrkeelEKYRNIIKPrvnswlefiplFKSLELSFEENAILKALCCWQTAHFKLEECDKENVRKQKSLLVQCLLKFCID 343
Cdd:smart00430  79 D-------RILSELVKP-----------LRELKLDDEEYALLKAIVLFNPAVPGLSEEGKEIVEKLQEKYANALHDYYLK 140

                          170
                   ....*....|....*.
gi 392898793   344 TYGeEEGPARAGNIIL 359
Cdd:smart00430 141 NYP-MNYPGRFAKLLL 155

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 392898793   3 CAICDSVALSLHFGAPSCKACAAFFRRTVALDITYDCITGTlDCEVNFERRMACKRCRYQKCIDNNMQRYLVQSK 77
Cdd:cd06960    1 CAVCGDRATGKHYGVLSCNGCKGFFRRSVRKNRTYTCRFGG-NCVVDKDKRNACRYCRFKKCLEVGMDPEAVQNE 74

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 392898793    3 CAICDSVALSLHFGAPSCKACAAFFRRTVALDITYDCiTGTLDCEVNFERRMACKRCRYQKCIDNNM 69
Cdd:pfam00105   2 CKVCGDKASGYHYGVLTCEGCKGFFRRSIQKNIVYTC-KFNKDCVIDKRNRNRCQYCRLKKCLEVGM 67

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 392898793  185 KQEYVMLFNYANTLPGFQELSNASQNFLFRIACGVDYVISSSYYT------LCIGTESNLLINQDGTYIQMMPLPLMGDE 258
Cdd:pfam00104  21 ERDLLLVAEWAKHFPEFQELPLEDQMALLKSFWLEWLRLEKAARSaklrrkKILGEDVLMISDDDAMKFVEDDSSWCTNY 100

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 392898793  259 PGTELMFTRKEELEKYRNIIKPrvnswlefiplFKSLELSFEENAILKALCCWQTAHFKLEECDKENVRKQKSLLVQCLL 338
Cdd:pfam00104 101 DLEQLLFFLPFFNSYFFELVKP-----------LRELNPDDEELAYLLAQLLFDYAGDGLSGEILEIVEKLQEKLANELH 169

                         170       180
                  ....*....|....*....|....*.
gi 392898793  339 KFCIDTYgeeegPARAGNIILFSSSI 364
Cdd:pfam00104 170 DYYVNKY-----SGRLAKLLKILPSL 190

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 392898793   3 CAICDSVALSLHFGAPSCKACAAFFRRTVALDITYDCITGTlDCEVNFERRMACKRCRYQKCIDNNMQRYLVQSK 77
Cdd:cd06960    1 CAVCGDRATGKHYGVLSCNGCKGFFRRSVRKNRTYTCRFGG-NCVVDKDKRNACRYCRFKKCLEVGMDPEAVQNE 74

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 392898793   3 CAICDSVALSLHFGAPSCKACAAFFRRTVALDITYDCiTGTLDCEVNFERRMACKRCRYQKCIDNNMQRYLV-------- 74
Cdd:cd07170    7 CLVCGDIASGYHYGVASCEACKAFFKRTIQGNIEYSC-PATNECEITKRRRKSCQACRFMKCLKVGMLKEGVrldrvrgg 85

                         90
                 ....*....|
gi 392898793  75 -QSKKGRPDA 83
Cdd:cd07170   86 rQKYKRRIDA 95

DNA-binding domain of estrogen receptor (ER) and estrogen related receptors (ERR) is composed of two C4-type zinc fingers; DNA-binding domains of estrogen receptor (ER) and estrogen related receptors (ERR) are composed of two C4-type zinc fingers. Each zinc finger contains a group of four Cys residues which co-ordinates a single zinc atom. ER and ERR interact with the palindromic inverted repeat, 5'GGTCAnnnTGACC-3', upstream of the target gene and modulate the rate of transcriptional initiation. ERR and ER are closely related and share sequence similarity, target genes, co-regulators and promoters. While ER is activated by endogenous estrogen, ERR lacks the ability to bind to estrogen. Estrogen receptor mediates the biological effects of hormone estrogen by the binding of the receptor dimer to estrogen response element of target genes. However, ERRs seem to interfere with the classic ER-mediated estrogen responsive signaling by targeting the same set of genes. ERRs and ERs exhibit the common modular structure with other nuclear receptors. 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 392898793   3 CAICDSVALSLHFGAPSCKACAAFFRRTVALDITYDCiTGTLDCEVNFERRMACKRCRYQKCIDNNMQR 71
Cdd:cd07155    1 CLVCGDIASGYHYGVASCEACKAFFKRTIQGNLGYSC-PSTSECEVDKKRRKSCQACRLQKCLKVGMLK 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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 392898793   3 CAICDSVALSLHFGAPSCKACAAFFRRTVALDITYDCiTGTLDCEVNFERRMACKRCRYQKCIDNNMQRYLV 74
Cdd:cd06961    2 CVVCGDKATGYHYRCITCEGCKGFFRRTVQKKLSYSC-KGEGKCEIDKVTRNQCQECRFKKCIAVGMAKDLV 72

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 392898793   3 CAICDSVALSLHFGAPSCKACAAFFRRTVALDITYDCiTGTLDCEVNFERRMACKRCRYQKCIDNNMQRYLVQSKK 78
Cdd:cd06956    3 CAICGDRASGKHYGVYSCEGCKGFFKRTVRKDLTYTC-RDNKDCLIDKRQRNRCQYCRYQKCLAMGMKREAVQEER 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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 392898793   1 MKCAICDSVALSLHFGAPSCKACAAFFRRTVALDITYDCItGTLDCEVNFERRMACKRCRYQKCIDNNM 69
Cdd:cd07168    7 KLCSICEDKATGLHYGIITCEGCKGFFKRTVQNKRVYTCV-GDGRCEITKAQRNRCQYCRFRKCIRKGM 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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 392898793   3 CAICDSVALSLHFGAPSCKACAAFFRRTVALDITYDCITGTlDCEVNFERRMACKRCRYQKCIDNNMQR 71
Cdd:cd07179    1 CRVCGGKSSGFHFGALTCEGCKGFFRRTELSSNSYVCPGGQ-NCAITPATRNACKSCRFRRCLAVGMSK 68

DNA-binding domain of the photoreceptor cell-specific nuclear receptor (PNR) like is composed of two C4-type zinc fingers; 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 392898793   3 CAICDSVALSLHFGAPSCKACAAFFRRTVALDITYDCITGTLDCEVNFERRMACKRCRYQKCIDNNMQRYLVQSKKG 79
Cdd:cd06957    1 CKVCGDKSYGKHYGVYCCDGCSCFFKRSVRKGIIYTCIAGNGNCVVDKARRNWCPFCRLQKCFAVGMNRAAVQEERG 77

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 392898793   3 CAICDSVALSLHFGAPSCKACAAFFRRTVALDITYDCITGTLDCEVNFERRMACKRCRYQKCIDNNMQRYLVQSKK 78
Cdd:cd06970    9 CRVCGDTSSGKHYGIYACNGCSGFFKRSVRRKLIYRCQAGTGMCPVDKAHRNQCQACRLKKCLQAGMNKDAVQNER 84

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 392898793   3 CAICDSVALSLHFGAPSCKACAAFFRRTVALDITYDCITGTlDCEVNFERRMACKRCRYQKCIDNNMQR 71
Cdd:cd07165    1 CKVCGDKASGYHYGVTSCEGCKGFFRRSIQKQIEYRCLRDG-KCEIIRLNRNRCQYCRFKKCLAAGMSK 68

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 392898793   3 CAICDSVALSLHFGAPSCKACAAFFRRTVALDITYDCITGTlDCEVNFERRMACKRCRYQKCIDNNMQRYLVQSKKGR 80
Cdd:cd07167    1 CPVCGDKVSGYHYGLLTCESCKGFFKRTVQNKKRYTCIENQ-NCQIDKTQRKRCPYCRFQKCLSVGMKLEAVRADRMR 77

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 392898793   3 CAICDSVALSLHFGAPSCKACAAFFRRTVALDITYDCITGTlDCEVNFERRMACKRCRYQKCIDNNMQRYLVQSKK 78
Cdd:cd06964    7 CFVCQDKSSGYHYGVSACEGCKGFFRRSIQKNMVYTCHRDK-NCIINKVTRNRCQYCRLQKCFEVGMSKESVRNDR 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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 392898793   3 CAICDSVALSLHFGAPSCKACAAFFRRTVALDITYDCITGTLDCEVNFERRMACKRCRYQKCIDNNMQR 71
Cdd:cd07158    1 CKVCGDKASGFHYGVHSCEGCKGFFRRTIQHNLTYRRCLNGGKCVIQRKNRNRCQYCRFKKCLSVGMSR 69

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 392898793 189 VMLFNYANTLPGFQELSNASQNFLFRIACGVDYVISSSYYTlCIGTESNLLINQDGTYIQMmplplmgDEPGTELMFtrK 268
Cdd:cd06157   12 LLIVEWAKSIPGFRELPLEDQIVLLKSFWLELLVLDLAYRS-YKNGLSLLLAPNGGHTDDD-------KEDEMKLLL--K 81

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 392898793 269 EELEKYRNiikprvnswlEFIPLFKSLELSFEENAILKALCCWQTAHFKLEECDKENVRKQKSLLvQCLLKFCIDTYGEE 348
Cdd:cd06157   82 GELIRLLF----------EFVNPLRALKLDDEEYALLKAIVLFSPDRKESLEDRKIVEELQERLL-EALQDYLRKNYPEE 150

                        170
                 ....*....|.
gi 392898793 349 EgPARAGNIIL 359
Cdd:cd06157  151 A-PSRFAKLLL 160

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        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 392898793   3 CAICDSVALSLHFGAPSCKACAAFFRRTVALDITYDCITGTlDCEVNFERRMACKRCRYQKCIDNNMQRYLVQSKKGRpd 82
Cdd:cd06966    3 CGVCGDKALGYNFNAITCESCKAFFRRNALKNKEFKCPFNE-SCEINVVTRRFCQKCRLDKCFAIGMKKEWIMSEEDK-- 79

                         90
                 ....*....|.
gi 392898793  83 ASTANGIENPT 93
Cdd:cd06966   80 SEKRQKIEENR 90

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).

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gi 392898793   3 CAICDSVALSLHFGAPSCKACAAFFRRTVALDITYDCiTGTLDCEVNFERRMACKRCRYQKCIDNNMQRYLVQ----SKK 78
Cdd:cd06968    8 CKICGDKSSGIHYGVITCEGCKGFFRRSQQNNVSYSC-PRQKNCLIDRTNRNRCQHCRLQKCLALGMSRDAVKfgrmSKK 86

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gi 392898793  79 GR 80
Cdd:cd06968   87 QR 88

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).

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gi 392898793   3 CAICDSVALSLHFGAPSCKACAAFFRRTVALDITYDC-ITGtlDCEVNFERRMACKRCRYQKCIDNNMQRYLV 74
Cdd:cd06955    9 CGVCGDRATGFHFNAMTCEGCKGFFRRSMKRKALFTCpFNG--DCRITKDNRRHCQACRLKRCVDIGMMKEFI 79

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).

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gi 392898793   3 CAICDSVALSLHFGAPSCKACAAFFRRTVALDITYDCITGTlDCEVNFERRMACKRCRYQKCIDNNMQ 70
Cdd:cd07161    4 CLVCGDRASGYHYNALTCEGCKGFFRRSVTKSAVYHCKYGR-ACEMDMYMRRKCQECRLKKCLSVGMR 70

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).

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gi 392898793   3 CAICDSVALSLHFGAPSCKACAAFFRRTVALDITYDCiTGTLDCEVNFERRMACKRCRYQKCIDNNM 69
Cdd:cd06963    1 CLICGDEASGCHYGVLTCGSCKVFFKRAAEGQHNYLC-AGRNDCIIDKIRRKNCPACRLRKCYQAGM 66

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).

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gi 392898793   3 CAICDSVALSLHFGAPSCKACAAFFRRTVALDITYDCITGTlDCEVNFERRMACKRCRYQKCIDNNM 69
Cdd:cd07173    6 CLICGDEASGCHYGALTCGSCKVFFKRAAEGKQKYLCASRN-DCTIDKFRRKNCPSCRLRKCFEAGM 71