ids like deoxycorticosterone or glucocorticoids like cortisol and progesterone. The affinity of the receptor for the cortisol is comparable to the affinity it has for aldosterone while the levels of circulating cortisol are many folds higher than those of aldosterone. The conversion of cortisol to the inactive cortisone by Hsd11b2 protects the receptor from being activated by a steroid hormone other than its physiological most relevant ligand. The expression of the enzyme is confined to certain tissues and minimal or absent in the myocardium and the hippocampus; in the nervous system cortisol may be the primary ligand and may act as an antagonist. Aldosterone is synthesized in the adrenal zona glomerulosa and its production is regulated by the selective expression of aldosterone synthase. The molecular mechanism that regulate its production/secretion are not well understood; angiotensin II signaling via receptor type 1 and also potassium concentration are thought to be major players. As a nuclear receptor member, Nr3c2 shares the signature presence of the three major functional domains: the N-terminal (NTD) domain with two AF-1 activation domains, the central DNA-binding (DBD) domain with two zinc fingers each containing one zinc ion tetrahedrally coordinated by four cysteine residues, and the C-terminal ligand-binding (LBD) domain that also contains the ligand-dependent AF-2 activation domain. The NTD domain of Nr3c2 is the longest of all steroid hormone receptors and the one with the lower extent of homology with the other receptors. In the absence of interacting proteins NTD is disordered; it can interact with the LBD in a ligand-dependent manner. The DBD is highly conserved among receptors and, in addition to DNA recognition, is also involved in receptor homo- and heterodimerization. LBD has a complex structural organization with eleven alpha-helices plus an additional unstructured helix 2 and four beta-strands. Helices 3, 4, 5 and 12 make up the AF-2 activation domain. The structures of the human LBD in complex with a compound, with spironolactone, with deoxycorticosterone, and with its agonist, aldosterone, are available. In the absence of ligands LBD interacts with chaperones and associated co-chaperone that sequester the receptor in the cytoplasmic milieu. They also maintain the receptor in a conformation suitable for specific ligand-binding and prevent non-specific activation. Upon ligand binding, LBD undergoes conformational changes that allow it to function as a docking platform for transcriptional co-regulators. Dissociation of some of the chaperones upon ligand binding leads to the translocation of the receptor to the nucleus, association with transcriptional activators or repressors to regulate the expression of target genes. The receptor also engages in interactions with chromatin and chromatin modifying factors. Nr3c2 is subject to post-translation modifications whose actual functional significance remains to be established. Deregulation of aldosterone signaling has been associated with cardiac and renal conditions. To see the ontology report for Gviewer, annotations and download, click here ...(less)