Nuclear hormone receptor, ligand-binding domain (IPR000536)

Short name: Nucl_hrmn_rcpt_lig-bd

Overlapping homologous superfamilies

Domain relationships



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, a linker region, and a C-terminal (Cter) ligand-binding domain (LBD), also called HOLI domain [PMID: 12538758, PMID: 15105832, PMID: 24844133].

The NR LBD plays a crucial role in ligand-mediated NR activity. In addition to its role is ligand recognition, the LBD also contains a ligand-dependent AF-2. Conformational changes in AF-2 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) [PMID: 24361687, PMID: 11050318, PMID: 9640540, PMID: 20723571].

The overall structure of NR LBD is composed of about 11-13 alpha-helices that are arranged into a three-layer antiparallel alpha-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. 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 alpha-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 [PMID: 11050318, PMID: 9640540, PMID: 20723571].

Contributing signatures

Signatures from InterPro member databases are used to construct an entry.
PROSITE profiles