Nuclear receptors (NRs), such as the receptors for steroids and thyroidhormones, retinoids and vitamin D3, are one of the most abundant classes oftranscriptional regulators in animals (metazoans). They regulate diversefunctions, such as homeostasis, reproduction, development and metabolism. Themost prominent feature differentiating them from other transcription factorsis their capacity to bind small hydrophobic molecules specifically. Theseligands constitute regulatory signals, which modify the NR transcriptionalactivity through conformational changes. Prototypical NRs share a commonstructural organization with a variable amino-terminal (Nter) domain thatcontains a constitutively active activation function (AF)-1, a conserved DNA-binding domain (DBD) consisting of two zinc fingers, alinker region, and a C-terminal (Cter) ligand-binding domain (LBD), alsocalled HOLI domain. The NR LBD plays a crucial role in ligand-mediated NRactivity. In addition to its role is ligand recognition, the LBD also containsa ligand-dependent AF-2. Conformational changes in AF-2 induced by variousligands can modulate interactions with conserved motifs of coregulatoryproteins. Specifically, the binding of ligands to the LBD determines therecruiting of transcriptional coregulators which triggers induction orrepression of target genes. The coregulators include coactivators like thep160 factors also referred to as the steroid receptor coactivators (SRC)family, and corepressors such as SMART (silencing mediator for retinoid andthyroid hormone receptors) and N-CoR (nuclear corepressor).The overall structure of NR LBD is composed of about 11-13 alpha-helices thatare arranged into a three-layer antiparallel alpha-helical sandwich with thethree long helices (helices 3, 7, and 10) forming the two outer layers. Themiddle layer of helices (helices 4, 5, 8 and 9) is present only in the tophalf of the domain but is missing from the bottom half, thereby creating acavity, so called ligand-binding pocket, for ligand binding in most receptors. The bound ligands stabilize the NR conformation throughdirect contacts with multiple structural elements including helices H3, H5,H6, H7, H10, and the loop preceeding the AF-2 helix. The C-terminal activationregion also forms an alpha-helix (AF-2), which can adopt multiple conformationdepending on the nature of the bound ligand. Helices 3,4 and 12 enclose ashallow hydrophobic groove which is the site for coregulator binding.Despite the conserved fold of NR LBDs, the ligand-binding pocket is the leastconserved region among different NR LBDs.