nuclear hormone receptors
Sunday 23 November 2003
Members of the nuclear receptor family share several structural features, including a central, highly conserved DNA-binding domain (DBD) that targets the receptor to specific DNA sequences, termed hormone response elements.
The C-terminal portion of the receptor includes the ligand-binding domain (LBD), which interacts directly with the hormone and contains a hormone-dependent transcriptional activation domain.
The LBD serves as a molecular switch that recruits coactivator proteins and activates the transcription of target genes when flipped into the active conformation by hormone binding (Kliewer et al., 1999).
Nuclear hormone receptors comprise a large family of proteins that shares a common structure and mechanism of action. Members of this family are regulated by small lipophilic signaling molecules such as steroid hormones, retinoids and thyroid hormone.
NRs are comprised of: an amino-terminal activation function domain AF-1; the DNA-binding domain; a hinge region; and a carboxy-terminal ligand-binding domain containing a second activation function, AF-2.
VDR acts primarily as a heterodimer with the retinoid X receptor (RXR) on vitamin D response elements (VDREs). It interacts with the transcription machinery and nuclear receptor coactivators or corepressors to regulate target gene activity.
NRs coregulators can be divided into 3 major classes:
1)ATP-dependent chromatin remodeling complexes that are involved in the location and association of nucleosomes with DNA;
2) Enzymes that catalyze modifications of histone tails to regulate histone-histone and histone-DNA interactions;
3) General transcription factors adaptors that bridge the functions between regulators and basal transcription factors.
nuclear receptors (NRs)
Benoit G, Malewicz M, Perlmann T. Digging deep into the pockets of orphan nuclear receptors: insights from structural studies. Trends Cell Biol. 2004 Jul;14(7):369-76. PMID: 15246430