Nuclear receptors (NRs), such as the receptors for steroids and thyroid
hormones, retinoids and vitamin D3, are one of the most abundant classes of
transcriptional regulators in animals (metazoans). They regulate diverse
functions, such as homeostasis, reproduction, development and metabolism. The
most prominent feature differentiating them from other transcription factors
is their capacity to bind small hydrophobic molecules specifically. These
ligands constitute regulatory signals, which modify the NR transcriptional
activity through conformational changes. Prototypical NRs share a common
structural organization with a variable amino-terminal (Nter) domain that
contains a constitutively active activation function (AF)-1, a conserved DNA-binding domain (DBD) consisting of two zinc fingers (see <PDOC00031>), a
linker region, and a C-terminal (Cter) ligand-binding domain (LBD), also
called HOLI domain. The NR LBD plays a crucial role in ligand-mediated NR
activity. In addition to its role is ligand recognition, the LBD also contains
a ligand-dependent AF-2. Conformational changes in AF-2 induced by various
ligands can modulate interactions with conserved motifs of coregulatory
proteins. Specifically, the binding of ligands to the LBD determines the
recruiting of transcriptional coregulators which triggers induction or
repression of target genes. The coregulators include coactivators like the
p160 factors also referred to as the steroid receptor coactivators (SRC)
family, and corepressors such as SMART (silencing mediator for retinoid and
thyroid hormone receptors) and N-CoR (nuclear corepressor) [1,2,3,4,5,6,7].
The overall structure of NR LBD is composed of about 11-13 α-helices that
are arranged into a three-layer antiparallel α-helical sandwich with the
three long helices (helices 3, 7, and 10) forming the two outer layers. The
middle layer of helices (helices 4, 5, 8 and 9) is present only in the top
half of the domain but is missing from the bottom half, thereby creating a
cavity, so called ligand-binding pocket, for ligand binding in most receptors
(see <PDB:1LBD>). The bound ligands stabilize the NR conformation through
direct contacts with multiple structural elements including helices H3, H5,
H6, H7, H10, and the loop preceeding the AF-2 helix. The C-terminal activation
region also forms an α-helix (AF-2), which can adopt multiple conformation
depending on the nature of the bound ligand. Helices 3,4 and 12 enclose a
shallow hydrophobic groove which is the site for coregulator binding.
Despite the conserved fold of NR LBDs, the ligand-binding pocket is the least
conserved region among different NR LBDs [5,6,7].
The profile we developed covers the entire NR LBD domain.
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