Ligand binding domain of hormone receptors;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
2QW4_C          88 SLEVIRKWAEKIPGFAELSPADQDLLLESAFLELFILRLAYRSKPGEGKLIFCSGLVLHRLQC-----ARGFGDWIDSIL 162
Cdd:smart00430   4 QLLLTVEWAKSFPGFRELSLEDQIVLLKSFWFELLLLELAYRSVKLKKELLLAPDGTYIRPDAvlelrKLFSPFLDRILS 83

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
2QW4_C         163 AFSRSLHSLLVDVPAFACLSALVLIT-DRHGLQEPRR--VEELQNRIASCLKEHVAAVaGEPQPASCLSRLLGKLPELRT 239
Cdd:smart00430  84 ELVKPLRELKLDDEEYALLKAIVLFNpAVPGLSEEGKeiVEKLQEKYANALHDYYLKN-YPMNYPGRFAKLLLILPELRK 162

                   .
2QW4_C         240 L 240
Cdd:smart00430 163 I 163

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).

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
2QW4_C       36 PANLLTSLVRAHLDSGPSTAKLDYSKFQELVLPHFGKEDAGDVQQFYDLLSGSLEVIRKWAEKIPGFAELSPADQDLLLE 115
Cdd:cd06945   1 PVSLITALVRAHVDSTPRKTDLDYSKIQENVDPVPPKPDSQQVQQFYDLLTGSVDVIRQWAEKIPGFKDLHREDQDLLLE 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
2QW4_C      116 SAFLELFILRLAYRSKPGEGKLIFCSGLVLHRLQCARGFGDWIDSILAFSRSLHSLL-VDVPAFACLSALVLITDRHGLQ 194
Cdd:cd06945  81 SAFLELFVLRLAYRSNPVDGKLVFCNGLVLHRLQCVRGFGEWLDSILAFSSSLQSLLlDDISAFCCLALLLLITERHGLK 160

                       170       180       190       200       210       220       230
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
2QW4_C      195 EPRRVEELQNRIASCLKEHVAAVAGEPQPASCLSRLLGKLPELRTLCTQGLQRIFYLKLEDLVPPPPIIDKIFMDTLPF 273
Cdd:cd06945 161 EPKKVEELQNKIISCLRDHVTSNYPGQDKPNRLSKLLLKLPELRTLSKKGLQRIFFLKLEDLLPPPPLIDKRFLDTLPF 239

Ligand binding domain of DHR38_like proteins, members of the nuclear receptor superfamily; The ligand binding domain of nuclear receptor DHR38_like proteins: DHR38 is a member of the steroid receptor superfamily in Drosophila. DHR38 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. At least four differentially expressed mRNA isoforms have been detected during development. Like other members of the nuclear receptor (NR) superfamily of ligand-activated transcription factors, DHR38 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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
2QW4_C       35 SPANLLTSLVRAHLDSGPSTAKLDYSKFQELVLPHFGKEDAGDVQQFYDLLSGSLEVIRKWAEKIPGFAELSPADQDLLL 114
Cdd:cd07072   1 PPVSLITALVRAHVDTSPDFANLDYSQYREPSPLEPPMSEAEKVQQFYSLLTSSIDVIKTFAEKIPGFPDLCKEDQELLF 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
2QW4_C      115 ESAFLELFILRLAYRSKPGEGKLIFCSGLVLHRLQCARGFGDWIDSILAFSRSLHSLLVDVPAFACLSALVLITDRHGLQ 194
Cdd:cd07072  81 QSASLELFVLRLAYRTAPEDTKLTFCNGVVLHKQQCQRSFGDWLHAILEFSKSLHAMDIDISAFACLCALTLITERHGLK 160

                       170       180       190       200       210       220       230
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
2QW4_C      195 EPRRVEELQNRIASCLKEHVAAVAGEPQPASCLSRLLGKLPELRTLCTQGLQRIFYLKLEDLVPPPPIIDKIFMDTLPF 273
Cdd:cd07072 161 EPHKVEQLQMKIISSLRDHVTYNAEAQKKPHYFSRLLGKLPELRSLSVQGLQRIFYLKLEDLVPAPPLIENMFVASLPF 239

The ligand binding domain (LBD) of retinoic acid receptor (RAR), a members of the nuclear receptor superfamily; The ligand binding domain (LBD) of retinoic acid receptor (RAR): Retinoic acid receptors are members of the nuclear receptor (NR) superfamily of ligand-regulated transcription factors. RARs mediate the biological effect of retinoids, including both naturally 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. RARs function as heterodimers with retinoic X receptors by binding to specific RAR response elements (RAREs) found in the promoter regions of retinoid target genes. In the absence of ligand, the RAR-RXR heterodimer recruits the corepressor proteins NCoR or AMRT, and associated factors such as histone deacetylases or DNA-methyltransferases, leading to an inactive condensed chromatin structure, preventing transcription. Upon ligand binding, the corepressors are released, and coactivator complexes such as histone acetyltransferase or histone arginine methyltransferases are recruited to activate transcription. There are three RAR subtypes (alpha, beta, gamma), originating from three distinct genes. For each subtype, several isoforms exist that differ in their N-terminal region, allowing retinoids to exert their pleiotropic effects. 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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
2QW4_C       39 LLTSLVRAHLDSGPSTAKLdySKFQELVLP-HFGKEDAGDVQQFYDLLSGSLEVIRKWAEKIPGFAELSPADQDLLLESA 117
Cdd:cd06937   2 LITKVRKAHQETFPSLCQL--GKYTTNSSAdQRVRLDLGLWDKFSELSTKCIIKIVEFAKRLPGFTTLTIADQITLLKAA 79

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
2QW4_C      118 FLELFILRLAYRSKPGEGKLIFCSGLVLHRLQC-ARGFGDWIDSILAFSRSLHSLLVDVPAFACLSALVLIT-DRHGLQE 195
Cdd:cd06937  80 CLDILILRICTRYTPEQDTMTFSDGLTLNRTQMhNAGFGPLTDLVFTFANQLLPLEMDDTEIGLLSAICLICgDRQDLEE 159

                       170       180       190       200       210       220       230
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
2QW4_C      196 PRRVEELQNRIASCLKEHVAavAGEPQPASCLSRLLGKLPELRTLCTQGLQRIFYLKLEDLVPPPPIIDKI 266
Cdd:cd06937 160 PDRVEKLQEPLLEALKIYAR--KRRPDKPHMFPKMLMKITDLRSISAKGAERVITLKMEIPGPMPPLISEM 228

The ligand binding domain of estrogen receptor and estrogen receptor-related receptors; The ligand binding domain of estrogen receptor (ER) and estrogen receptor-related receptors (ERRs): Estrogen receptors are a group of receptors which are 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. ERRs are 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. Like other members of the nuclear receptor (NR) superfamily of ligand-activated transcription factors, ER and ERRs 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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
2QW4_C       83 DLLSGSLEVIRKWAEKIPGFAELSPADQDLLLESAFLELFILRLAYRSKPGEGKLIFCSGLVLHRLQCA-RGFGDWIDSI 161
Cdd:cd07068  34 DLADRELVHIISWAKHIPGFSDLSLNDQMHLLQSAWLEILMLGLVWRSLPHPGKLVFAPDLLLDREQARvEGLLEIFDML 113

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
2QW4_C      162 LAFSRSLHSLLVDVPAFACLSALVLI-TDRHGLQEPRRVEELQNRIASCLKEHVAAVAGEPQPaSCLSRLLGKLPELRTL 240
Cdd:cd07068 114 LQLVRRFRELGLQREEYVCLKAIILAnSDVRHLEDREAVQQLRDAILDALVDVEAKRHGSQQP-RRLAQLLLLLPHLRQA 192

                       170
                ....*....|....*...
2QW4_C      241 CTQGLQRIFYLKLEDLVP 258
Cdd:cd07068 193 SNKGVRHLYSVKCEGKVP 210

Ligand-binding domain of nuclear receptor family 1; Ligand-binding domain (LBD) of nuclear receptor (NR) family 1: This is one of the major subfamily of nuclear receptors, including thyroid receptor, retinoid acid receptor, ecdysone receptor, farnesoid X receptor, vitamin D receptor, and other related receptors. Nuclear receptors form a superfamily of ligand-activated transcription regulators, which regulate various physiological functions, from development, reproduction, to homeostasis and metabolism in animals (metazoans). The family contains not only receptors for known ligands but also orphan receptors for which ligands do not exist or have not been identified. NRs share a common structural organization with a central well conserved DNA binding domain (DBD), a variable N-terminal domain, a flexible hinge and a C-terminal ligand binding domain (LBD).

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
2QW4_C       78 VQQFYDLLSGSLEVIRKWAEKIPGFAELSPADQDLLLESAFLELFILRLAYRSKPGEGKLIFCSGLVLHRLQCAR-GFGD 156
Cdd:cd06929   4 FDHFTEIMTVAIRRVVEFAKRIPGFRELSQEDQIALLKGGCFEILLLRSATLYDPEKNSLTFGDGKGNSRDVLLNgGFGE 83

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
2QW4_C      157 WIDSILAFSRSLHSLLVDVPAFACLSALVLIT-DRHGLQEPRRVEELQNRIASCLKEHVAAVagEPQPASCLSRLLGKLP 235
Cdd:cd06929  84 FIEPLFEFAEKMNKLQLDDNEYALLTAIVLFSpDRPGLQDVDTVEKLQERLLEALQRYLKVN--HPDAPQMFAKLLKKLT 161

                       170
                ....*....|...
2QW4_C      236 ELRTLCTQGLQRI 248
Cdd:cd06929 162 ELRTLNELHAELL 174

The ligand binding domain (LBD) of the Ecdysone receptor, a member of the nuclear receptors super family; The ligand binding domain (LBD) of the ecdysone receptor: The ecdysone receptor (EcR) belongs to the superfamily of nuclear receptors (NRs) of ligand-dependent transcription factors. Ecdysone receptor 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 ecdysone receptor are ecdysteroids#the endogenous steroidal hormones found in invertebrates. In addition, insecticide bisacylhydrazine used against pests has shown to act on EcR. EcR must be dimerised with a USP for high-affinity ligand binding to occur. The ligand binding triggers a conformational change in the C-terminal part of the EcR ligand-binding domain that leads to transcriptional activation of genes controlled by EcR. Like other members of the nuclear receptor (NR) superfamily of ligand-activated transcription factors, ec dysone 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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
2QW4_C       88 SLEVIRKWAEKIPGFAELSPADQDLLLESAFLELFILRLAYRSKPGEGKLIFCSGLVLHRLQCAR-GFGDWIDSILAFSR 166
Cdd:cd06938  51 TVQLIVEFAKRLPGFDKLSREDQITLLKACSSEVMMLRVARRYDAKTDSIVFANNQPYTRDSYRKaGMGDSAEDLFRFCR 130

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
2QW4_C      167 SLHSLLVDVPAFACLSALVLITDRHGLQEPRRVEELQNRIASCLKEHVAAVAgEPQPASCLSRLLGKLPELRTLCTQGLQ 246
Cdd:cd06938 131 AMCSMKVDNAEYALLTAIVIFSDRPGLLQPKKVEKIQEIYLEALRAYVDNRR-PPSQRVIFAKLLSILTELRTLGNQNSE 209

                       170
                ....*....|....
2QW4_C      247 RIFYLKLEDLVPPP 260
Cdd:cd06938 210 MCFSLKLKNRKLPP 223

The ligand binding domain of Liver X receptors, a family of nuclear receptors of ligand-activated transcription factors; The ligand binding domain of Liver X receptors: Liver X receptors (LXRs) belong to a family of nuclear receptors of ligand-activated transcription factors. LXRs operate as cholesterol sensors which protect from cholesterol overload by stimulating reverse cholesterol transport from peripheral tissues to the liver and its excretion in the bile. Oxidized cholesterol derivatives or oxysterols were identified as specific ligands for LXRs. Upon ligand binding a conformational change leads to recruitment of co-factors, which stimulates expression of target genes. Among the LXR target genes are several genes involved in cholesterol efflux from peripheral tissues such as the ATP-binding-cassette transporters ABCA1, ABCG1 and ApoE. There are two LXR isoforms in mammals, LXRalpha and LXRbeta. LXRalpha is expressed mainly in the liver, intestine, kidney, spleen, and adipose tissue, whereas LXRbeta is ubiquitously expressed at lower level. Both LXRalpha and LXRbeta function as heterodimers with the retinoid X receptor (RX R) which may be activated by either LXR ligands or 9-cis retinoic acid, a specific RXR ligand. The LXR/RXR complex binds to a liver X receptor response element (LXRE) in the promoter region of target genes. LXR has typical NR modular structure with a central well conserved DNA binding domain (DBD), a variable N-terminal domain, a flexible hinge and the ligand binding domain (LBD) at the C-terminal.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
2QW4_C       81 FYDLLSGSLEVIRKWAEKIPGFAELSPADQDLLLESAFLELFILRLAYRSKPGEGKLIFCSGLVLHRLQCAR--GFGDWI 158
Cdd:cd06954  48 FTELAILSVQEIVDFAKQLPGFLTLTREDQIALLKASTIEVMLLETARRYNPESEAITFLKDFPYSRDDFARagLQVEFI 127

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
2QW4_C      159 DSILAFSRSLHSLLVDVPAFACLSAL-VLITDRHGLQEPRRVEELQNRIASCLkeHVAAVAGEPQPASCLSRLLGKLPEL 237
Cdd:cd06954 128 NPIFEFSKSMRELQLDDAEYALLIAInIFSADRPNVQDHHRVERLQETYVEAL--HSYIKIKRPSDRLMFPRMLMKLVSL 205

                       170       180
                ....*....|....*....|...
2QW4_C      238 RTLCTQGLQRIFYLKLEDLVPPP 260
Cdd:cd06954 206 RTLSSVHSEQVFALRLQDKKLPP 228

The ligand binding domain of Retinoid-related orphan receptors, of the nuclear receptor superfamily; The ligand binding domain (LBD) of Retinoid-related orphan receptors (RORs): Retinoid-related orphan receptors (RORs) are transcription factors belonging to the nuclear receptor superfamily. 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. Transcription regulation by RORs is mediated through certain corepressors, as well as coactivators. There are three subtypes of retinoid-related orphan receptors (RORs), alpha, beta, and gamma that 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 su ggested that cholesterol or a cholesterol derivative is the natural ligand 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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
2QW4_C       85 LSGSLEVIRKWAEKIPGFAELSPADQDLLLESAFLELFILRLAYRSKPGEGKLIFCSGLVLHRLQCARGFGDWIDSILAF 164
Cdd:cd06939  57 ITEAIQYVVEFAKRIPGFMELCQNDQIVLLKAGSLEVVLVRMSRAFNPSNNTVLFDGKYAPIDLFKSLGCDDLISAVFDF 136

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
2QW4_C      165 SRSLHSLLVDVPAFACLSALVLIT-DRHGLQEPRRVEELQNRIASCLKEHVAAVAGEPqpaSCLSRLLGKLPELRTLCTQ 243
Cdd:cd06939 137 AKSLCELKLTEDEIALFSALVLISaDRPGLQEKRKVEKLQQKIELALRHVLQKNHGDD---TILTKLLAKMPTLRALCSL 213

                       170       180
                ....*....|....*....|....*...
2QW4_C      244 GLQRIFYLKLEDLVPP----PPIIDKIF 267
Cdd:cd06939 214 HMEKLQKFKQSYPDIVhlefPPLYKELF 241

The ligand binding domain of REV-ERB receptors, members of the nuclear receptor superfamily; The ligand binding domain (LBD) of REV-ERB receptors: REV-ERBs 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. The LBD domain of REV-ERB is unusual in the nuclear receptor family by lacking the AF-2 region that is responsible for coactivator interaction. REV-ERBs act as constitutive repressors because of their inability to bind coactivators. REV-ERB receptors can bind to two classes of DNA response elements as either a monomer or heterodimer, indicating functional diversity. When bound to the DNA, they recruit corepressors (NcoR/histone deacetylase 3) to the promoter, resulting in repression of the target gene. The porphyrin heme has been demonstrated to function as a ligand for REV-ERB. 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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
2QW4_C       90 EVIrKWAEKIPGFAELSPADQDLLLESAFLELFILRLAYRSKPGEGKLIFCSGLVLHR--LQCArGFGDWIDSILAFSRS 167
Cdd:cd06940  27 EVV-EFAKRIPGFRDLSQHDQVTLLKAGTFEVLMVRFASLFDAKERSVTFLSGQKYSVddLHSM-GAGDLLNSMFDFSEK 104

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
2QW4_C      168 LHSLLVDVPAFACLSALVLIT-DRHGLQEPRRVEELQNRIASCLKEHVAavAGEPQPASCLSRLLGKLPELRTLCT 242
Cdd:cd06940 105 LNSLQLSDEEMGLFTAVVLVSaDRSGLENVNLVEALQETLIRALRTLIA--KNHPNEPSIFTKLLLKLPDLRTLNN 178

Ligand binding domain of chicken ovalbumin upstream promoter transcription factors, a member of the nuclear receptor family; The ligand binding domain of chicken ovalbumin upstream promoter transcription factors (COUP-TFs): COUP-TFs are orphan members of the steroid/thyroid hormone receptor superfamily. They are expressed in many tissues and are involved in the regulation of several important biological processes, such as neurogenesis, organogenesis, cell fate determination, and metabolic homeostasis. In mammals two isoforms named COUP-TFI and COUP-TFII have been identified. Both genes show an exceptional homology and overlapping expression patterns, suggesting that they may serve redundant functions. Although COUP-TF was originally characterized as a transcriptional activator of the chicken ovalbumin gene, COUP-TFs are generally considered to be repressors of transcription for other nuclear hormone receptors, such as retinoic acid receptor (RAR), thyroid hormone receptor (TR), vitamin D receptor (VDR), peroxisome proliferator activated receptor (PPAR), and hepatocyte nuclear factor 4 (HNF4). Like other members of the nuclear receptor (NR) superfamily of ligand-activated transcription factors, COUP-TFs have a central well cons erved 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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
2QW4_C       95 WAEKIPGFAELSPADQDLLLESAFLELFILRLAYRSKPGE-GKLIFCSGLVLHRLQcARGFGDWIDSILAFS---RSLHS 170
Cdd:cd06948  49 WARNIPFFPDLQVTDQVALLRLSWSELFVLNAAQCCMPLHvAPLLAAAGLHASPMS-ADRVVAFMDHIRIFQeqvEKLKA 127

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
2QW4_C      171 LLVDVPAFACLSALVLIT-DRHGLQEPRRVEELQNRIASCLKEHVAavAGEPQPASCLSRLLGKLPELRTLCTQGLQRIF 249
Cdd:cd06948 128 LHVDSAEFSCLKAIVLFTsDACGLSDPAHIESLQEKSQCALEEYVR--TQYPNQPTRFGKLLLRLPSLRTVSSSVIEQLF 205

                       170       180
                ....*....|....*....|....
2QW4_C      250 YLKLEDLVPPPPIIDKIFMDTLPF 273
Cdd:cd06948 206 FVRLVGKTPIETLIRDMLLSGSSF 229

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).

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
2QW4_C       94 KWAEKIPGFAELSPADQDLLLESAFLELFILRLAYRSKPGEGK-LIFCSGLVLHRLQCARGFgdwIDSILAFSRSL---H 169
Cdd:cd06950  44 KWAKSIPAFSTLPFRDQLILLEESWSELFLLGAAQWSLPLDSCpLLAVPGLSPDNTEAERTF---LSEVRALQETLsrfR 120

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
2QW4_C      170 SLLVDVPAFACLSALVLI-TDRHGLQEPRRVEELQNRIASCLKEHVAAvAGEPQPAScLSRLLGKLPELRTLCTQGLQRI 248
Cdd:cd06950 121 QLRVDATEFACLKAIVLFkPETRGLKDPAQVEALQDQAQLMLNKHIRT-RYPTQPAR-FGKLLLLLPSLRFISSSTIEEL 198

                ....
2QW4_C      249 FYLK 252
Cdd:cd06950 199 FFKK 202

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
2QW4_C       88 SLEVIRKWAEKIPGFAELSPADQDLLLESAFLELFILRLAYRSKPGEGKLIFCSGLVLHRLQCARGFGDWIDSIL-AFSR 166
Cdd:cd06931  44 QLLVLVEWAKYIPAFCELPLDDQVALLRAHAGEHLLLGVARRSMPYKDILLLGNDLIIPRHCPEPEISRVANRILdELVL 123

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
2QW4_C      167 SLHSLLVDVPAFACLSALVLIT-DRHGLQEPRRVEELQNRIASCLKEHVAavagEPQPASC--LSRLLGKLPELRTLCTQ 243
Cdd:cd06931 124 PLRDLNIDDNEYACLKAIVFFDpDAKGLSDPQKIKRLRFQVQVSLEDYIN----DRQYDSRgrFGELLLLLPTLQSITWQ 199

                       170
                ....*....|
2QW4_C      244 GLQRIFYLKL 253
Cdd:cd06931 200 MIEQIQFARL 209

The ligand binding domain of Farnesoid X receptor:a member of the nuclear receptor superfamily of ligand-activated transcription factors; The ligand binding domain (LBD) of Farnesoid X receptor: Farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily of ligand-activated transcription factors. FXR is highly expressed in the liver, the intestine, the kidney, and the adrenals. FXR plays key roles in the regulation of bile acid, cholesterol, triglyceride, and glucose metabolism. Evidences show that it also regulates liver regeneration. Upon binding of ligands, such as bile acid, an endogenous ligand, FXRs bind to FXR response elements (FXREs) either as a monomer or as a heterodimer with retinoid X receptor (RXR), and regulate the expression of various genes involved in bile acid, lipid, and glucose metabolism. There are two FXR genes (FXRalpha and FXRbeta) in mammals. A single FXRalpha gene encodes four isoforms resulting from differential use of promoters and alternative splicing. FXRbeta is a functional receptor in mice, rats, rabbits and dogs, but is a pseudogene in humans and primates. Like other members of the nuclear receptor (NR) superfamily, farnesoid X 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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
2QW4_C       89 LEVIRKWAEKIPGFAELSPADQDLLLESAFLELFILRLA--YRSKPGEGKlifcSGLVLHRLQCARGFGDWIDSILAFSR 166
Cdd:cd06936  49 VQVLVEFTKGLPGFETLDHEDQIALLKGSAVEAMFLRSAqiYNKKLPAGH----ADLLEERIRSSGISDEFITPMFNFYK 124

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
2QW4_C      167 SLHSLLVDVPAFACLSAL-VLITDRHGLQEPRRVEELQNRIASCLkeHVAAVAGEPQPASCLSRLLGKLPELRTL 240
Cdd:cd06936 125 SMGELKMTQEEYALLTAItILFPDRPYLKDKEAVEKLQEPLLDLL--QKFCKLYHPEDPQHFACLLGRLTELRTL 197

The ligand binding domain of nuclear receptor steroidogenic factor 1, a member of nuclear receptor superfamily; The ligand binding domain of nuclear receptor steroidogenic factor 1 (SF-1): SF-1, a member of the nuclear hormone receptor superfamily, is an essential regulator of endocrine development and function and is considered a master regulator of reproduction. Most nuclear receptors function as homodimer or heterodimers, however SF-1 binds to its target genes as a monomer, recognizing the variations of the DNA sequence motif, T/CCA AGGTCA. SF-1 functions cooperatively with other transcription factors to modulate gene expression. Phospholipids have been determined as potential ligands of SF-1. Like other members of the nuclear receptor (NR) superfamily of ligand-activated transcription factors, SF-1 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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
2QW4_C       92 IRKWAEKIPGFAELSPADQDLLLESAFLELFILRLAYR--SKPGEGKLIFCSGLVLHRLQCARGFGDWIDSILAFSRS-- 167
Cdd:cd07070  54 IVDWARRCMVFKELEVADQMTLLQNCWSELLVFDHIYRqvQHGKEGSILLVTGQEVELSTVAAQAGSLLHSLVLRAQElv 133

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
2QW4_C      168 --LHSLLVDVPAFACLSALVLIT-DRHGLQEPRRVEELQNRIASCLKEHvaAVAGEPQPASCLSRLLGKLPELRTLCTQG 244
Cdd:cd07070 134 lqLHALQLDRQEFVCLKFLILFSlDVKFLNNHSLVKDAQEKANAALLDY--TLCHYPHCGDKFQQLLLRLVEVRALSMQA 211

                       170
                ....*....|....
2QW4_C      245 LQRIFYLKLEDLVP 258
Cdd:cd07070 212 KEYLYHKHLGNEMP 225

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
2QW4_C       95 WAEKIPGFAELSPADQDLLLESAFLELFILRLAYRSkpGEGKLIFCSGLVLHRLQCA-----------RGFGDWIDSILA 163
Cdd:cd06952  40 WARSIPAFQALGAETQTSLVRACWPELFTLGLAQCS--QQLSLPTILAAIINHLQTSiqqdklsadkvKQVMEHINKLQE 117

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
2QW4_C      164 FSRSLHSLLVDVPAFACLSALVLITDRHGLQEPRR-VEELQNRIASCLKEHVAAvaGEPQPASCLSRLLGKLPELRTLCT 242
Cdd:cd06952 118 FVNSMQKLDVDDHEYAYLKAIVLFSPDHPGQELRQqIEKLQEKALMELRDYVGK--TYPEDEYRLSKLLLRLPPLRSLSP 195

                       170
                ....*....|.
2QW4_C      243 QGLQRIFYLKL 253
Cdd:cd06952 196 AITEELFFAGL 206

The ligand binding domain of DAX1 protein, a nuclear receptor lacking DNA binding domain; The ligand binding domain of DAX1-like proteins: This orphan nuclear receptor family includes DAX1 (dosage-sensitive sex reversal adrenal hypoplasia congenita critical region on chromosome X gene 1) and the Small Heterodimer Partner (SHP). Both receptors have a typical ligand binding domain, but lack the DNA binding domain, typical to almost all of the nuclear receptors. They function as a transcriptional coregulator by directly interacting with other nuclear receptors. DAX1 and SHP can form heterodimers with each other, as well as with many other nuclear receptors. In addition, DAX1 can also form homodimers. DAX1 plays an important role in the normal development of several hormone-producing tissues. SHP has shown to regulate a variety of target genes.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
2QW4_C       98 KIPGFAELSPADQDLLLESAFLELFILRLAYRSKPGEGKLI----FCSGLVLHRLQCARGFGDW------------IDSI 161
Cdd:cd06951  41 NLPCFTYLPPDDQLRLLRRSWAPLLLLGLAQDKVPFDTVEVpapsILCEILTGAEMHWGGTPPPtltmppcipladVQDI 120

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
2QW4_C      162 LAFSRSLHSLLVDVPAFACLSALVLITDRHGLQEPRRVEELQNRIASCLKEHVAAVagEPQPASCLSRLLGKLPELRTLC 241
Cdd:cd06951 121 QQFLMKCWSLDLDCKEYAYLKGAVLFTPVPPLLCPHYIEALQKEAQQALNEHTMMT--RPLEQLRSARLLLMLSLLRGIK 198

                ....*....
2QW4_C      242 TQGLQRIFY 250
Cdd:cd06951 199 TEPVTELFF 207

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).

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
2QW4_C       94 KWAEKIPGFAELSPADQDLLLESAFLELFILRLAYRS-KPGEGK-LIFCSGLVL--HRLQCARgFGDWIDSILAFSRSLH 169
Cdd:cd06947  46 KWAKALPGFRNLHLDDQMTLIQYSWMSLMVFALGWRSyKHVNSQmLYFAPDLVFneQRMHQSA-MYSLCLGMRQISQEFV 124