Nuclear hormone receptor proteins form a class of ligand-activated proteins, when they combined with specific DNA sequences, they can act as switches to be transcribed in the nucleus. These switches control the development and differentiation of the skin, bones and behavioral centers in the brain, as well as regulate reproductive tissues. Nuclear hormone receptors are ligand-activated transcription factors that regulate gene expression by interacting with specific DNA sequences upstream of their target genes. As early as 1968, a two-step mechanism of action was proposed based on the observation of the stage of receptors. The first step is activated by binding of hormones; the second step involves receptor binding to DNA and transcriptional regulation.
A hormone response component (HRE) could be a specific DNA sequence that a receptor acknowledges with markedly inflated affinity and generally two consensus hexameric half-sites half-sites. The identity of a response component resides in three features: the sequence of the bottom pairs within the half-site, the amounts of base pairs between the half-sites and also the relative orientation of the 2 half-sites. Therfore, every receptor macromolecule compound that binds the DNA has got to acknowledge the sequence, spacing and orientation of the half-sites among their response component. The nuclear hormone receptor proteins area unit composed of many domains that area unit totally differentially preserved between the varied receptors and have different roles: a variable N-terminal region, a preserved DNA binding domain (DBD), a variable hinge region, a preserved matter binding domain (LBD), and a variable C-terminal region.
DNA Binding Domain (DBD)
The central DBD is chargeable for targeting the receptors to their hormone response components (HRE). The DNA binding domain, classified as a type-II atomic number 30 finger motif, has two subdomains, every containing atomic number 30 particle coordinated by four amino acid residues, followed by associate alpha-helix. The DBD binds as a compound with every chemical compound recognizing a six nucleotides sequence of DNA. The reading helix of every chemical compound makes sequence specific contacts within the major groove of the DNA at each half-site. These contacts enable the compound to scan the sequence, spacing and orientation of the half-sites among its response component, and therefore discriminate between sequences. These proteins exhibit, however, a flexibility in recognizing DNA sequences and additionally settle for a range of amino-acid substitutions in their reading helix while not abolishing binding.
Figure 1. Structure of the human progesterone receptor DNA-binding domain dimer (cyan and green) complexed with double strained DNA (magenta). Zinc atoms of are depicted as grey spheres.
Ligand Binding Domain (LBD)
Moderately conserved in sequence and highly conserved in structure between the various nuclear receptors. The structure of the LBD is referred to as an alpha helical sandwich fold in which three anti parallel alpha helices (the "sandwich filling") are flanked by two alpha helices on one side and three on the other (the "bread"). The ligand binding cavity is within the interior of the LBD and just below three anti parallel alpha helical sandwich "filling". Along with the DBD, the LBD contributes to the dimerization interface of the receptor and in addition, binds coactivator and corepressor proteins. The LBD also contains the activation function 2 (AF-2) whose action is dependent on the presence of bound ligand.
Figure 2. Crystallographic structure of the ligand binding domain.
1. Dorina K.; et al. Unbinding of retinoic acid from its receptor studied by steered molecular dynamics. Biophysical Journal. 1999,76:188-197.
2. Dorina K.; et al. Binding of the estrogen receptor to DNA: The role of waters. Biophysical Journal. 1999,73: 557-570.