{PDOC51843}
{PS51843; NR_LBD}
{BEGIN}
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* Nuclear receptor (NR) ligand-binding (LBD) domain profile *
*************************************************************

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 in ligand recognition, the LBD also contains
a ligand-dependent  AF-2  region.  Conformational  changes  in the AF-2 region
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 alpha-helices that
are arranged  into  a three-layer antiparallel alpha-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 alpha-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.

-Sequences known to belong to this class detected by the profile: ALL.
-Other sequence(s) detected in Swiss-Prot: NONE.
-Last update: October 2017 / First entry.

[ 1] Robinson-Rechavi M., Escriva Garcia H., Laudet V.
     "The nuclear receptor superfamily."
     J. Cell Sci. 116:585-586(2003).
     PubMed=12538758
[ 2] Brelivet Y., Kammerer S., Rochel N., Poch O., Moras D.
     "Signature of the oligomeric behaviour of nuclear receptors at the
     sequence and structural level."
     EMBO Rep. 5:423-429(2004).
     PubMed=15105832; DOI=10.1038/sj.embor.7400119
[ 3] Xie P., Yuan C., Wang C., Zou X.T., Po Z., Tong H.B., Zou J.M.
     "Molecular cloning and tissue distribution of peroxisome
     proliferator-activated receptor-alpha (PPARalpha) and gamma
     (PPARgamma) in the pigeon (Columba livia domestica)."
     Br. Poult. Sci. 55:136-142(2014).
     PubMed=24844133; DOI=10.1080/00071668.2014.889281
[ 4] Tsuji M.
     "Local motifs involved in the canonical structure of the
     ligand-binding domain in  the nuclear receptor superfamily."
     J. Struct. Biol. 185:355-365(2014).
     PubMed=24361687; DOI=10.1016/j.jsb.2013.12.007
[ 5] Bourguet W., Germain P., Gronemeyer H.
     "Nuclear receptor ligand-binding domains: three-dimensional
     structures, molecular  interactions and pharmacological
     implications."
     Trends Pharmacol. Sci. 21:381-388(2000).
     PubMed=11050318
[ 6] Moras D., Gronemeyer H.
     "The nuclear receptor ligand-binding domain: structure and function."
     Curr. Opin. Cell Biol. 10:384-391(1998).
     PubMed=9640540
[ 7] Jin L., Li Y.
     "Structural and functional insights into nuclear receptor signaling."
     Adv. Drug. Deliv. Rev. 62:1218-1226(2010).
     PubMed=20723571; DOI=10.1016/j.addr.2010.08.007

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