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Nuclear hormone receptors are ligand-activated transcription factors that regulate gene expression by interacting with specific DNA sequences upstream of their target genes. In vertebrates, these proteins regulate diverse biological processes such as pattern formation, cellular differentiation and homeostasis [1,2,3,4,5,6].

Classical nuclear hormone receptors contain two conserved regions, the hormone binding domain and a DNA-binding domain (DBD) that is composed of two C4-type zinc fingers. The DBD is responsible for targeting the receptors to their hormone response elements (HRE). It binds as a dimer with each monomer recognizing a six base pair sequence of DNA. The vast majority of targets contain the same 5'-AGGTCA-3' consensus sequence [7]. In some cases a less conserved C-terminal extension of the core DBD confers the DNA selectivity [8].

The two zinc fingers fold to form a single structural domain (see <PDB:1HCQ>) [9,10]. The structure consists of two helices perpendicular to each other. A zinc ion, coordinated by four conserved cysteines, holds the base of a loop at the N terminus of each helix. The helix of each monomer makes sequence specific contacts in the major groove of the DNA.

Proteins known to contain a nuclear hormone receptor DNA-binding domain are listed below:

• Androgen receptor (AR).
• Estrogen receptor (ER).
• Glucocorticoid receptor (GR).
• Mineralocorticoid receptor (MR).
• Progesterone receptor (PR).
• Retinoic acid receptors (RARs and RXRs).
• Thyroid hormone receptors (TR) α and β.
• The avian erythroblastosis virus oncogene v-erbA, derived from a cellular thyroid hormone receptor.
• Vitamin D3 receptor (VDR).
• Insects ecdysone receptor (EcR).
• COUP transcription factor (also known as ear-3), and its Drosophila homolog seven-up (svp).
• Hepatocyte nuclear factor 4 (HNF-4), which binds to DNA sites required for the transcription of the genes for α-1-antitrypsin, apolipoprotein CIII and transthyretin.
• Ad4BP, a protein that binds to the Ad4 site found in the promoter region of steroidogenic P450 genes.
• Apolipoprotein AI regulatory protein-1 (ARP-1), required for the transcription of apolipoprotein AI.
• Peroxisome proliferator activated receptors (PPAR), transcription factors specifically activated by peroxisome proliferators. They control the peroxisomal β-oxidation pathway of fatty acids by activating the gene for acyl-CoA oxidase.
• Drosophila protein knirps (kni), a zygotic gap protein required for abdominal segmentation of the Drosophila embryo.
• Drosophila protein ultraspiracle (usp) (or chorion factor 1), which binds to the promoter region of s15 chorion gene.
• Human estrogen receptor related genes 1 and 2 (err1 and err2).
• Human erbA related gene 2 (ear-2).
• Mammalian NGFI-B (NAK1, nur/77, N10).
• Mammalian NOT/nurR1/RNR-1.
• Drosophila protein embryonic gonad (egon).
• Drosophila knirps-related protein (knrl).
• Drosophila protein tailless (tll).
• Drosophila 20-oh-ecdysone regulated protein E75.
• Insects Hr3.
• Insects Hr38.
• Caenorhabditis elegans cnr-8, cnr-14, and odr-7
• Caenorhabditis elegans hypothetical proteins B0280.8, EO2H1.7 and K06A1.4.

As a signature pattern for this family of proteins, we took the most conserved residues, the first 27, of the DNA-binding domain. We also developed a profile that spans the whole domain.

April 2006 / Pattern revised.

PROSITE methods (with tools and information) covered by this documentation:

NUCLEAR_REC_DBD_2, PS51030; Nuclear hormone receptors DNA-binding domain profile  (MATRIX)

Sequences known to belong to this class detected by the profile: ALL Other sequence(s) detected in Swiss-Prot: NONE.

• Domain architecture view of Swiss-Prot proteins matching PS51030 • Retrieve an alignment of Swiss-Prot true positive hits:   Clustal format, color, condensed view  / Clustal format, color  / Clustal format, plain text  / Fasta format • Retrieve the sequence logo from the alignment • Taxonomic tree view of all Swiss-Prot/TrEMBL entries matching PS51030 • Retrieve a list of all Swiss-Prot/TrEMBL entries matching PS51030 • Scan Swiss-Prot/TrEMBL entries against PS51030 • view ligand binding statistics

Matching PDB structures: 1A6Y 1BY4 1CIT 1DSZ ... [ALL]

NUCLEAR_REC_DBD_1, PS00031; Nuclear hormones receptors DNA-binding region signature  (PATTERN)

Consensus pattern: C-x(2)-C-x(1,2)-[DENAVSPHKQT]-x(5,6)-[HNY]-[FY]-x(4)-C-x(2)-C-x(2)-F(2)-x-R The 4 C's are zinc ligands Sequences known to belong to this class detected by the profile: ALL Other sequence(s) detected in Swiss-Prot: NONE.

• Retrieve an alignment of Swiss-Prot true positive hits:   Clustal format, color, condensed view  / Clustal format, color  / Clustal format, plain text  / Fasta format • Retrieve the sequence logo from the alignment • Taxonomic tree view of all Swiss-Prot/TrEMBL entries matching PS00031 • Retrieve a list of all Swiss-Prot/TrEMBL entries matching PS00031 • Scan Swiss-Prot/TrEMBL entries against PS00031 • view ligand binding statistics

Matching PDB structures: 1A6Y 1BY4 1CIT 1DSZ ... [ALL]

1	Authors	Gronemeyer H., Laudet V.
	Source	Protein Prof. 2:1173-1308(1995).

2	Authors	Evans R.M.
	Title	The steroid and thyroid hormone receptor superfamily.
	Source	Science 240:889-895(1988).
	PubMed ID	3283939

3	Authors	Gehring U.
	Source	Trends Biochem. Sci. 12:399-402(1987).

4	Authors	Beato M.
	Title	Gene regulation by steroid hormones.
	Source	Cell 56:335-344(1989).
	PubMed ID	2644044

5	Authors	Segraves W.A.
	Title	Something old, some things new: the steroid receptor superfamily in Drosophila.
	Source	Cell 67:225-228(1991).
	PubMed ID	1913821

6	Authors	Laudet V., Haenni C., Coll J., Catzeflis F., Stehelin D.
	Title	Evolution of the nuclear receptor gene superfamily.
	Source	EMBO J. 11:1003-1013(1992).
	PubMed ID	1312460

7	Authors	Stunnenberg H.G.
	Title	Mechanisms of transactivation by retinoic acid receptors.
	Source	BioEssays 15:309-315(1993).
	PubMed ID	8393666

8	Authors	Zhao Q., Khorasanizadeh S., Miyoshi Y., Lazar M.A., Rastinejad F.
	Title	Structural elements of an orphan nuclear receptor-DNA complex.
	Source	Mol. Cell 1:849-861(1998).
	PubMed ID	9660968

9	Authors	Schwabe J.W.R., Neuhaus D., Rhodes D.
	Title	Solution structure of the DNA-binding domain of the oestrogen receptor.
	Source	Nature 348:458-461(1990).
	PubMed ID	2247153
	DOI	10.1038/348458a0

10	Authors	Schwabe J.W.R., Chapman L., Finch J.T., Rhodes D.
	Source	Cell 75:567-578(1993).

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