HOLI Ligand binding domain of hormone receptors
SMART ACC:	SM000430
Description:	-
InterPro ACC:	IPR000536
InterPro abstract:	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 … expand 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 organisation with a variable N-terminal 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 ligand-binding domain (LBD), also called HOLI domain [ PUBMED:12538758 PUBMED:15105832 PUBMED:24844133 ]. The NR LBD plays a crucial role in ligand-mediated NR activity. In addition to its role is ligand recognition, the LBD also containsa ligand-dependent AF-2. Conformational changes in AF-2 induced by various ligands can modulate interactions with conserved motifs of coregulatoryproteins. 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) [ PUBMED:24361687 PUBMED:11050318 PUBMED:9640540 PUBMED:20723571 ]. 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. The bound ligands stabilize the NR conformation through direct contacts with multiple structural elements including helices H3, H5, H6, H7, H10, and the loop proceeding the AF-2 helix. The C-terminal activation region also forms an α-helix (AF-2), which can adopt multiple conformationdepending 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 [ PUBMED:11050318 PUBMED:9640540 PUBMED:20723571 ]. collapse
Family alignment:	View the Family alignment or the Alignment consensus sequence
There are 28 310 HOLI domains in 28 124 proteins in SMART's NRDB database.

Taxonomic distribution of proteins containing HOLI domains

The tree below includes only several representative species and genera. The complete taxonomic breakdown of all proteins containing HOLI domains can be accessed here. Click the counts or percentage values to display the corresponding proteins.

Predicted cellular role

Binding / catalysis:	Hormones

Relevant references for this domain

Primary literature for the HOLI domain is listed below. Automatically-derived, secondary literature is also available.

Disease genes where sequence variants are found in this domain

UniRef sequences and OMIM curated human diseases associated with missense mutations within the HOLI domain.

Protein	Description	Disease / phenotype
HNF4A_HUMAN		OMIM:600281 : MODY, type 1
		OMIM:125850 : {Diabetes mellitus, noninsulin-dependent}
		OMIM:125853 : no description
ANDR_HUMAN		OMIM:313700 : Androgen insensitivity, several forms ; Spinal and bulbar muscular atrophy of Kennedy
ANDR_HUMAN		OMIM:313200 : Prostate cancer ; Perineal hypospadias ; Breast cancer, male, with Reifenstein syndrome
GCR_HUMAN		OMIM:138040 : Cortisol resistance
VDR_HUMAN		OMIM:601769 : Rickets, vitamin D-resistant
VDR_HUMAN		OMIM:277440 : ?Osteoporosis, involutional
NR2E3_HUMAN		OMIM:604485 : Enhanced S-cone syndrome
		OMIM:268100 : Retinitis pigmentosa, late onset
		OMIM:268000 : no description
ESR1_HUMAN		OMIM:133430 : Breast cancer ; Estrogen resistance
NR0B1_HUMAN		OMIM:300200 : Adrenal hypoplasia, congenital, with hypogonadotropic hypogonadism ; Dosage-sensitive sex reversal
NR0B1_HUMAN		OMIM:300018 : no description
THB_HUMAN		OMIM:190160 : Thyroid hormone resistance
		OMIM:274300 : no description
		OMIM:188570 : no description
PPARG_HUMAN		OMIM:601487 : Obesity, severe
		OMIM:601665 : [Obesity, protection against] ; Diabetes mellitus, insulin-resistant, with acanthosis nigricans and hypertension
		OMIM:604367 : no description

KEGG pathways involving proteins which contain this domain

This information is based on the mapping of SMART genomic protein database to KEGG orthologous groups. Percentages are related to the number of proteins containing a HOLI domain which could be assigned to a KEGG orthologous group, and not all proteins containing HOLI domains. Please note that proteins can be included in multiple pathways, ie. the numbers below will not add to 100%.

KEGG pathways

Some of these pathways are included in the interactive Pathways Explorer overview maps. Select an overview map and click the button below to highlight them in iPath.

KEGG orthologous groups

Some of these KOs are included in the interactive Pathways Explorer overview maps. Select an overview map and click the button below to highlight them in iPath.

3D structures in PDB containing this domain

Links to other resources describing this domain

Pfam	hormone_rec
InterPro	IPR000536