The agonistic effects of endogenous hormones can also be mimicked by certain synthetic ligands, for example, the glucocorticoid receptor anti-inflammatory drug dexamethasone

The activity of endogenous ligands (such as the hormones estradiol and testosterone) when bound to their cognate nuclear receptors is normally to upregulate gene expression. This stimulation of gene expression by the ligand is referred to as an agonist response.

Agonists

Depending on the receptor involved, the chemical structure of the ligand and the tissue that is being affected, nuclear receptor ligands may display dramatically diverse effects ranging in a spectrum from agonism to antagonism to inverse agonism.

Binding of antagonist ligands to nuclear receptors in contrast induces a conformation of the receptor that preferentially binds corepressor proteins. These proteins, in turn, recruit histone deacetylases (HDACs), which strengthens the association of histones to DNA, and therefore represses gene transcription.

Corepressors

Binding of agonist ligands to nuclear receptors induces a conformation of the receptor that preferentially binds coactivator proteins. These proteins often have an intrinsic histone acetyltransferase (HAT) activity, which weakens the association of histones to DNA, and therefore promotes gene transcription.

Coactivators

NRs bound to hormone response elements recruit a significant number of other proteins (referred to as transcription coregulators) that facilitate or inhibit the transcription of the associated target gene into mRNA. The functions of these coregulators are varied and include chromatin remodeling (making the target gene either more or less accessible to transcription) or a bridging function to stabilize the binding of other coregulatory proteins. NRs may bind specifically to a number of coregulator proteins, and thereby influence cellular mechanisms of signal transduction both directly, as well as indirectly.

Coregulatory proteins

This figure depicts the mechanism of a class II NRs, which, regardless of ligand-binding status, is located in the nucleus bound to DNA. For the purpose of illustration, the nuclear receptor shown here is the thyroid hormone receptor (TR) heterodimerized to the RXR. In the absence of ligand, the TR is bound to corepressor protein. Ligand binding to TR causes a dissociation of corepressor and recruitment of coactivator protein, which, in turn, recruits additional proteins such as RNA polymerase that are responsible for transcription of downstream DNA into RNA and eventually protein, which results in a change in cell function.

Дата добавления: 2014-01-14