Nuclear receptors are ligand-activated
transcription factors that bind nonpolar regulatory
molecules. Because ligands are nonpolar, they can just diffuse
across the plasma membrane to bind to the nuclear receptor that is
an intracellular receptor. Nuclear receptor
ligands include steroid hormones, thyroid hormones,
retinoic acid, and vitamin D3, but also fatty
acids and phospholipids.
The DNA sequences for two steroid hormone receptors (the
glucocorticoid receptor and the estrogen receptor) were first
determined in the mid-1980s. The structural homology between these
two receptors caused investigators to hypothesize that they were
part of a family of proteins. Subsequently, more members of the
family were cloned based on sequence homology. There are a total
of 48 nuclear receptor family members in the human genome. For
some of these receptors, the physiological function and endogenous
natural ligand are not known: these are termed orphan
receptors. Some of the original orphan receptors have
now had their endogenous ligands identified ("adopted
orphans"). An important group of receptors in this class are
the PPAR receptors, which are involved in metabolic
regulation, and are important drug targets. Fibrates (which
bind to the receptor PPAR-alpha) are a class of drugs used
to treat dyslipidemia in order to lower the risk of cardiovascular
disease. Thiazolidinediones (TZDs; which bind to the
receptor PPAR-gamma) are drugs that promote insulin
sensitivity in the treatment of type 2 diabetes mellitus.
The basic molecular structure of a nuclear receptor is shown in a linear form in the figure below. All the nuclear receptors contain three important domains: a transcriptional regulation domain, a DNA binding domain, and a ligand binding domain.
This next figure diagrams how signaling works for many nuclear receptors.
In the absence of ligand, an inhibitory complex associates with
the ligand-binding domain. Ligand binding causes a
conformational change so that the inhibitory complex (red)
dissociates. This allows the receptor to bind to DNA, and
associate with the coregulator protein complex (green), a group of
proteins that regulate gene transcription. Genes that are
regulated by nuclear receptors contain particular DNA sequences (response
elements) in their promoters, where the nuclear receptor
The coregulator proteins that associate with the receptor may be activators or repressors of transcription. One particular receptor may associate with different groups of coregulators in different cell types. This differential recruitment of coregulators is thought to underlie the action of drugs known as receptor modulators. Receptor modulators are drugs that act as agonists in some tissues, while acting as antagonists in other tissues. An example is the selective estrogen receptor modulator (SERM) known as raloxifene. Raloxifene is used to prevent loss of bone density in postmenopausal women. Raloxifene acts as an estrogen receptor agonist in bone tissue, but acts as an estrogen receptor antagonist in breast and uterine tissue.