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).

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1052139208   1 DLSLYDQVRLLESCWMEVLMVGLMWRSIDHPGKLIFAPDLVLDRDEGKCVEGILEIFDMLLAMTSRLRELKLQHKEYLCV 80
Cdd:cd06949    60 DLSLHDQVHLLESAWLELLMLGLVWRSMEHPGKLLFAPDLLLDRNQGSCVEGMVEIFDMLLATASRFRELQLQREEYVCL 139

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gi 1052139208  81 KAM 83
Cdd:cd06949   140 KAI 142

Ligand binding domain of Estrogen receptor, which are activated by the hormone 17beta-estradiol (estrogen); The ligand binding domain (LBD) of Estrogen receptor (ER): Estrogen receptor, a member of nuclear receptor superfamily, is activated by the hormone estrogen. Estrogen regulates many physiological processes including reproduction, bone integrity, cardiovascular health, and behavior. The main mechanism of action of the estrogen receptor is as a transcription factor by binding to the estrogen response element of target genes upon activation by estrogen and then recruiting coactivator proteins which are responsible for the transcription of target genes. Additionally some ERs may associate with other membrane proteins and can be rapidly activated by exposure of cells to estrogen. Like other members of the nuclear receptor (NR) superfamily of ligand-activated transcription factors, ER has a central well conserved DNA binding domain (DBD), a variable N-terminal domain, a flexible hinge and a C-terminal ligand binding domain (LBD). The C-terminal LBD also contains AF-2 activation motif, the dimerization motif, and part of the nuclear localization region. Estrogen receptor has been linked to aging, cancer, obesity and other diseases.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1052139208   1 DLSLYDQVRLLESCWMEVLMVGLMWRSIDHPGKLIFAPDLVLDRDEGKCVEGILEIFDMLLAMTSRLRELKLQHKEYLCV 80
Cdd:cd06949    60 DLSLHDQVHLLESAWLELLMLGLVWRSMEHPGKLLFAPDLLLDRNQGSCVEGMVEIFDMLLATASRFRELQLQREEYVCL 139

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gi 1052139208  81 KAM 83
Cdd:cd06949   140 KAI 142

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

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1052139208   1 DLSLYDQVRLLESCWMEVLMVGLMWRSIDHPGKLIFAPDLVLDRDEGKCVEGIL------------------EIFDMLLA 62
Cdd:pfam00104  39 ELPLEDQMALLKSFWLEWLRLEKAARSAKLRRKKILGEDVLMISDDDAMKFVEDdsswctnydleqllfflpFFNSYFFE 118

                          90       100
                  ....*....|....*....|.
gi 1052139208  63 MTSRLRELKLQHKEYLCVKAM 83
Cdd:pfam00104 119 LVKPLRELNPDDEELAYLLAQ 139

Ligand binding domain of Estrogen receptor, which are activated by the hormone 17beta-estradiol (estrogen); The ligand binding domain (LBD) of Estrogen receptor (ER): Estrogen receptor, a member of nuclear receptor superfamily, is activated by the hormone estrogen. Estrogen regulates many physiological processes including reproduction, bone integrity, cardiovascular health, and behavior. The main mechanism of action of the estrogen receptor is as a transcription factor by binding to the estrogen response element of target genes upon activation by estrogen and then recruiting coactivator proteins which are responsible for the transcription of target genes. Additionally some ERs may associate with other membrane proteins and can be rapidly activated by exposure of cells to estrogen. Like other members of the nuclear receptor (NR) superfamily of ligand-activated transcription factors, ER has a central well conserved DNA binding domain (DBD), a variable N-terminal domain, a flexible hinge and a C-terminal ligand binding domain (LBD). The C-terminal LBD also contains AF-2 activation motif, the dimerization motif, and part of the nuclear localization region. Estrogen receptor has been linked to aging, cancer, obesity and other diseases.

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gi 1052139208   1 DLSLYDQVRLLESCWMEVLMVGLMWRSIDHPGKLIFAPDLVLDRDEGKCVEGILEIFDMLLAMTSRLRELKLQHKEYLCV 80
Cdd:cd06949    60 DLSLHDQVHLLESAWLELLMLGLVWRSMEHPGKLLFAPDLLLDRNQGSCVEGMVEIFDMLLATASRFRELQLQREEYVCL 139

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gi 1052139208  81 KAM 83
Cdd:cd06949   140 KAI 142

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

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gi 1052139208   1 DLSLYDQVRLLESCWMEVLMVGLMWRSIDHPGKLIFAPDLVLDRDEGKCVeGILEIFDMLLAMTSRLRELKLQHKEYLCV 80
Cdd:cd06946    55 SLSLNDQMSLLQSAWMEILTLGVVFRSLPFNGELVFAEDFILDEELAREA-GLLELYSACLQLVRRLQRLRLEKEEYVLL 133

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gi 1052139208  81 KAM 83
Cdd:cd06946   134 KAL 136

The ligand binding domain of the retinoid X receptor and Ultraspiracle, members of nuclear receptor superfamily; The ligand binding domain of the retinoid X receptor (RXR) and Ultraspiracle (USP): This family includes two evolutionary related nuclear receptors: retinoid X receptor (RXR) and Ultraspiracle (USP). RXR is a nuclear receptor in mammalian and USP is its counterpart in invertebrates. The native ligand of retinoid X receptor is 9-cis retinoic acid (RA). RXR functions as a DNA binding partner by forming heterodimers with other nuclear receptors including CAR, FXR, LXR, PPAR, PXR, RAR, TR, and VDR. RXRs can play different roles in these heterodimers. It 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. Ultraspiracle (USP) plays similar roles as DNA binding partner of other nuclear rec eptors in invertebrates. USP has no known high-affinity ligand and is thought to be a silent component in the heterodimeric complex with partner receptors. Like other members of the nuclear receptor (NR) superfamily of ligand-activated transcription factors, RXR and USP 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).

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gi 1052139208   1 DLSLYDQVRLLESCWMEVLMVGLMWRSIDHPGKLIFAPDLVLDRDEGKCVeGILEIFDMLLA-MTSRLRELKLQHKEYLC 79
Cdd:cd06943    58 ELPLDDQVILLRAGWNELLIAAFAHRSIAVKDGILLATGLHLHRNSAHQA-GVGAIFDRILTeLVVKMRDLKMDRTELGC 136

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gi 1052139208  80 VKA 82
Cdd:cd06943   137 LRA 139

Ligand binding domain of the progesterone receptor, a member of the nuclear hormone receptor; The ligand binding domain of the progesterone receptor (PR): PR is a member of the nuclear receptor superfamily of ligand dependent transcription factors, mediating the biological actions of progesterone. PR functions in a variety of biological processes including development of the mammary gland, regulating cell cycle progression, protein processing, and metabolism. When no binding hormone is present the carboxyl terminal inhibits transcription. Binding to a hormone induces a structural change that removes the inhibitory action. After progesterone binds to the receptor, PR forms a dimer and the complex enters the nucleus where it interacts with the hormone response element (HRE) in the promoters of progesterone responsive genes and alters their transcription. In addition, rapid actions of PR that occur independent of transcription, have also been observed in several tissues like brain, liver, mammary gland and spermatozoa. There are two natural PR isoforms called PR-A and PR-B. PR-B has an additional stretc h of 164 amino acids at the N terminus. The extra domain in PR-B performs activation functions by recruiting coactivators that could not be recruited by PR-A. Like other members of the nuclear receptor (NR) superfamily of ligand-activated transcription factors, PR has a central well conserved DNA binding domain (DBD), a variable N-terminal domain, a flexible hinge and a C-terminal ligand binding domain (LBD). The LBD is not only involved in binding to progesterone, but also involved in coactivator binding and dimerization.

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gi 1052139208   1 DLSLYDQVRLLESCWMEVLMVGLMWRSIDH--PGKLIFAPDLVLDRDEGKCVegilEIFDMLLAMTSRLRE---LKLQHK 75
Cdd:cd07074    56 NLHIDDQITLIQYSWMSLMVFGLGWRSYKHvsGQMLYFAPDLILNEQRMKES----SFYSLCLTMWQIPQEfvkLQVSQE 131

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gi 1052139208  76 EYLCVKAM 83
Cdd:cd07074   132 EFLCMKAL 139

The ligand binding domain of Nurr1 and related nuclear receptor proteins, members of nuclear receptor superfamily; The ligand binding domain of nuclear receptor Nurr1_like: This family of nuclear receptors, including Nurr1, Nerve growth factor-induced-B (NGFI-B) and DHR38 are involved in the embryo development. Nurr1 is a transcription factor that is expressed in the embryonic ventral midbrain and is critical for the development of dopamine (DA) neurons. Structural studies have shown that the ligand binding pocket of Nurr1 is filled by bulky hydrophobic residues, making it unable to bind to ligands. Therefore, it belongs to the class of orphan receptors. However, Nurr1 forms heterodimers with RXR and can promote signaling via its partner, RXR. NGFI-B is an early immediate gene product of embryo development that is rapidly produced in response to a variety of cellular signals including nerve growth factor. It is involved in T-cell-mediated apoptosis, as well as neuronal differentiation and function. NGFI-B regulates transcription by binding to a specific DNA target upstream of its target genes and regulating the rate of tr anscriptional initiation. Another group of receptor in this family is DHR38. DHR38 is the Drosophila homolog to the vertebrate NGFI-B-type orphan receptor. It interacts with the USP component of the ecdysone receptor complex, suggesting that DHR38 might modulate ecdysone-triggered signals in the fly, in addition to the ECR/USP pathway. Nurr1_like proteins exhibit a modular structure that is characteristic for nuclear receptors; they 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 1052139208   1 DLSLYDQVRLLESCWMEVLMVGLMWRSIDHPGKLIFAPDLVLDRDEgkCVEGILEIFDMLLAMTSRLRELKLQHKEYLCV 80
Cdd:cd06945    69 DLHREDQDLLLESAFLELFVLRLAYRSNPVDGKLVFCNGLVLHRLQ--CVRGFGEWLDSILAFSSSLQSLLLDDISAFCC 146

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gi 1052139208  81 KAM 83
Cdd:cd06945   147 LAL 149

Ligand binding domain of nuclear hormone receptors:glucocorticoid receptor, mineralocorticoid receptor , progesterone receptor, and androgen receptor; The ligand binding domain of GR_like nuclear receptors: This family of NRs includes four distinct, but closely related nuclear hormone receptors: glucocorticoid receptor (GR), mineralocorticoid receptor (MR), progesterone receptor (PR), and androgen receptor (AR). These four receptors play key roles in 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 use multiple signaling pathways and share similar functional mechanisms. The dominant signaling pathway is via direct DNA binding and transcriptional regulation of target genes. Another mechanism is via protein-protein interactions, mainly with other transcription factors such as nuclear factor-kappaB and activator protein-1, to regulate gene expression patterns. Both pathways can up-regulate or down-regulate gene expression and require ligand activation of the receptor and recruitment of other cofactors such as chaperone proteins and coregulator proteins. Like other members of the nuclear receptor (NR) superfamily of ligand-activated transcription factors, GR, MR, PR, and AR share the same modular structure 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).

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gi 1052139208   2 LSLYDQVRLLESCWMEVLMVGLMWRSIDH--PGKLIFAPDLVLDRDEGKcvegILEIFDMLLAMTSRLRE---LKLQHKE 76
Cdd:cd06947    57 LHLDDQMTLIQYSWMSLMVFALGWRSYKHvnSQMLYFAPDLVFNEQRMH----QSAMYSLCLGMRQISQEfvrLQVTYEE 132

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gi 1052139208  77 YLCVKAM 83
Cdd:cd06947   133 FLCMKVL 139

Ligand binding domain of the glucocorticoid receptor, a member of the nuclear receptor superfamily; The ligand binding domain of the glucocorticoid receptor (GR): GR is a ligand-activated transcription factor belonging to the nuclear receptor superfamily. It binds with high affinity to cortisol and other glucocorticoids. GR is expressed in almost every cell in the body and regulates genes controlling a wide variety of processes including the development, metabolism, and immune response of the organism. In the absence of hormone, the glucocorticoid receptor (GR) is complexes with a variety of heat shock proteins in the cytosol. The binding of the glucocorticoids results in release of the heat shock proteins and transforms it to its active state. One mechanism of action of GR is by direct activation of gene transcription. The activated form of GR forms dimers, translocates into the nucleus, and binds to specific hormone responsive elements, activating gene transcription. GR can also function as a repressor of other gene transcription activators, such as NF-kappaB and AF-1 by directly binding to them, and bloc king the expression of their activated genes. Like other members of the nuclear receptor (NR) superfamily of ligand-activated transcription factors, GR has a central well conserved DNA binding domain (DBD), a variable N-terminal domain, a flexible hinge and a C-terminal ligand binding domain (LBD). The LBD also functions for dimerization and chaperone protein association.

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gi 1052139208   1 DLSLYDQVRLLESCWMEVLMVGLMWRSIDHPGK--LIFAPDLVLDRDEGKcVEGILEIFDMLLAMTSRLRELKLQHKEYL 78
Cdd:cd07076    56 NLHLDDQMTLLQYSWMFLMAFALGWRSYRQSNGnlLCFAPDLIINEQRMT-LPCMYDQCKHMLYVSSELHRLQVSYEEYL 134

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gi 1052139208  79 CVKAM 83
Cdd:cd07076   135 CMKTL 139

Ligand binding domain of the mineralocorticoid receptor, a member of the nuclear receptor superfamily; The ligand binding domain of the mineralocorticoid receptor (MR): MR, also called aldosterone receptor, is a member of nuclear receptor superfamily involved in the regulation of electrolyte and fluid balance. The receptor is activated by mineralocorticoids such as aldosterone and deoxycorticosterone as well as glucocorticoids, like cortisol and cortisone. Binding of its ligand results in its translocation to the cell nucleus, homodimerization and binding to hormone response elements (HREs) present in the promoter of MR controlled genes. This results in the recruitment of the coactivators and the transcription of the activated genes. MR is expressed in many tissues and its activation results in the expression of proteins regulating electrolyte and fluid balance. Like other members of the nuclear receptor (NR) superfamily of ligand-activated transcription factors, MR has a central well conserved DNA binding domain (DBD), a variable N-terminal domain, a flexible hinge and a C-terminal ligand binding domain (LBD ). The LBD, in addition to binding ligand, contains a ligand-dependent activation function-2 (AF-2).

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gi 1052139208   1 DLSLYDQVRLLESCWMEVLMVGLMWRSIDHPGK--LIFAPDLVLDRDEGKCVegilEIFDMLLAM---TSRLRELKLQHK 75
Cdd:cd07075    56 NLPLEDQITLIQYSWMCLSSFALSWRSYKHTNSqfLYFAPDLVFNEERMHQS----AMYELCQGMhqiSLQFVRLQLTFE 131

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gi 1052139208  76 EYLCVKAM 83
Cdd:cd07075   132 EYTIMKVL 139

The ligand binding domain of FTZ-F1 like nuclear receptors; The ligand binding domain of FTZ-F1 like nuclear receptors: 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 required at several stages of development. Particularly, FTZ-F1 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 a monomer. 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).

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gi 1052139208   1 DLSLYDQVRLLESCWMEVLMVGLMWRSIDH--PGKLIFAPDLVLDRDEGKCVEGILeIFDMLLAMT---SRLRELKLQHK 75
Cdd:cd06944    66 ELKVDDQMKLLQNCWSELLVLDHIYRQVHHgkEDSILLVTGQEVDLSTLASQAGLG-LSSLVDRAQelvNKLRELQFDRQ 144

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gi 1052139208  76 EYLCVK 81
Cdd:cd06944   145 EFVCLK 150

The ligand binding domain of Tailless-like proteins, orphan nuclear receptors; The ligand binding domain of the photoreceptor cell-specific nuclear receptor (PNR) like family: This family includes photoreceptor cell-specific nuclear receptor (PNR), Tailless (TLX), and related receptors. 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. 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, TLX and PNR 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).

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gi 1052139208   2 LSLYDQVRLLESCWMEVLMVGLMWRSIDHPGKLIFAPDLVLDRDEGKCVEGILEIfDMLLAMTSRLRELKLQHKEYLCVK 81
Cdd:cd06950    55 LPFRDQLILLEESWSELFLLGAAQWSLPLDSCPLLAVPGLSPDNTEAERTFLSEV-RALQETLSRFRQLRVDATEFACLK 133

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gi 1052139208  82 A 82
Cdd:cd06950   134 A 134