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PROSITE documentation PDOC51843
Nuclear receptor (NR) ligand-binding (LBD) domain profile


Nuclear receptors (NRs), such as the receptors for steroids and thyroid hormones, retinoids and vitamin D3, are one of the most abundant classes of transcriptional regulators in animals (metazoans). They regulate diverse functions, such as homeostasis, reproduction, development and metabolism. The most prominent feature differentiating them from other transcription factors is their capacity to bind small hydrophobic molecules specifically. These ligands constitute regulatory signals, which modify the NR transcriptional activity through conformational changes. Prototypical NRs share a common structural organization with a variable amino-terminal (Nter) domain that contains a constitutively active activation function (AF)-1, a conserved DNA-binding domain (DBD) consisting of two zinc fingers (see <PDOC00031>), a linker region, and a C-terminal (Cter) ligand-binding domain (LBD), also called HOLI domain. The NR LBD plays a crucial role in ligand-mediated NR activity. In addition to its role in ligand recognition, the LBD also contains a ligand-dependent AF-2 region. Conformational changes in the AF-2 region induced by various ligands can modulate interactions with conserved motifs of coregulatory proteins. Specifically, the binding of ligands to the LBD determines the recruiting of transcriptional coregulators which triggers induction or repression of target genes. The coregulators include coactivators like the p160 factors also referred to as the steroid receptor coactivators (SRC) family, and corepressors such as SMART (silencing mediator for retinoid and thyroid hormone receptors) and N-CoR (nuclear corepressor) [1,2,3,4,5,6,7].

The overall structure of NR LBD is composed of about 11-13 α-helices that are arranged into a three-layer antiparallel α-helical sandwich with the three long helices (helices 3, 7, and 10) forming the two outer layers. The middle layer of helices (helices 4, 5, 8 and 9) is present only in the top half of the domain but is missing from the bottom half, thereby creating a cavity, so called ligand-binding pocket, for ligand binding in most receptors (see <PDB:1LBD>). The bound ligands stabilize the NR conformation through direct contacts with multiple structural elements including helices H3, H5, H6, H7, H10, and the loop preceeding the AF-2 helix. The C-terminal activation region also forms an α-helix (AF-2), which can adopt multiple conformation depending on the nature of the bound ligand. Helices 3,4 and 12 enclose a shallow hydrophobic groove which is the site for coregulator binding. Despite the conserved fold of NR LBDs, the ligand-binding pocket is the least conserved region among different NR LBDs [5,6,7].

The profile we developed covers the entire NR LBD domain.

Last update:

October 2017 / First entry.


Technical section

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

NR_LBD, PS51843; Nuclear receptor (NR) ligand-binding (LBD) domain profile  (MATRIX)


1AuthorsRobinson-Rechavi M. Escriva Garcia H. Laudet V.
TitleThe nuclear receptor superfamily.
SourceJ. Cell Sci. 116:585-586(2003).
PubMed ID12538758

2AuthorsBrelivet Y. Kammerer S. Rochel N. Poch O. Moras D.
TitleSignature of the oligomeric behaviour of nuclear receptors at the sequence and structural level.
SourceEMBO Rep. 5:423-429(2004).
PubMed ID15105832

3AuthorsXie P. Yuan C. Wang C. Zou X.T. Po Z. Tong H.B. Zou J.M.
TitleMolecular cloning and tissue distribution of peroxisome proliferator-activated receptor-alpha (PPARalpha) and gamma (PPARgamma) in the pigeon (Columba livia domestica).
SourceBr. Poult. Sci. 55:136-142(2014).
PubMed ID24844133

4AuthorsTsuji M.
TitleLocal motifs involved in the canonical structure of the ligand-binding domain in the nuclear receptor superfamily.
SourceJ. Struct. Biol. 185:355-365(2014).
PubMed ID24361687

5AuthorsBourguet W. Germain P. Gronemeyer H.
TitleNuclear receptor ligand-binding domains: three-dimensional structures, molecular interactions and pharmacological implications.
SourceTrends Pharmacol. Sci. 21:381-388(2000).
PubMed ID11050318

6AuthorsMoras D. Gronemeyer H.
TitleThe nuclear receptor ligand-binding domain: structure and function.
SourceCurr. Opin. Cell Biol. 10:384-391(1998).
PubMed ID9640540

7AuthorsJin L. Li Y.
TitleStructural and functional insights into nuclear receptor signaling.
SourceAdv. Drug. Deliv. Rev. 62:1218-1226(2010).
PubMed ID20723571

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