X Receptor Beta
Kelly Heilman '12 and Crystal Piras '12
X receptors are ligand
activated transcription factors that are part of the protein family on
mainly through recruitment of coactivators. Liver X receptors are
oxysterol ligands, also called oxygenated cholesterol
LXR's are involved in the regulation of
cholesterol, and therefore are of interest in treating cardiovascular
such as atherosclerosis.
LXRα and LXR
lipogenesis in the liver through LXR
including ChREBP (carbohydrate response element binding protein) and
(sterol regulatory element binding protein 1c). These
proteins are involved
in production of LDL cholesterol and Glucose
metabolism in the liver.
Most of the
current research on these receptors is done on the pretext of
developing LXR ligands
that may treat or prevent cardiovascular disease without causing
hepatic side effects.
known LXR ligands include the
endogenous ligand 24(S),25-epoxycholesterol (eCH) and synthetic
and GW3965 (both non-sterol).
of nuclear receptors,
liver X receptor β has three layers of alpha helices.
unit of this crystal consists of an LXR homodimer complexed
with its coactivator SRC-1.
monomer is characterized by 10 total helices
and the AF2
AF2 helix interacts with the ligand binding pocket as well as the
transcription cofactor SRC-1 and is a domain common to Nuclear
make up the dimer interface.
features of the LXR β include a long helix 1,
is made up of about 18 amino acid residues.
β has a large ligand
binding pocket that is 830 Å3.
Ligand Binding Pocket
β is a ligand activated
transcription factor that binds a variety of endogenous and ectopic ligands. Each
ligand is thought to
differentially regulate transcription of different genes. For
this reason, current work is investigating ligands that would
preferentially prevent genes
cardiovascular disease from being transcribed. The ligand binding
is a large
up of three layers of alpha helices: Helices
3, 5, 6, 7,
11, and 12.
completely lined with hydrophobic residues except for His-435 located in helix 11.
hydrophobic residues of helix 3 are Phe-268,
Thr-272, Leu-274, Ala-275.
helix 5 Ile-309,
line the LBD.
6 contributes to the LBD but it does not contribute any amino acid
the lining of the cavity. Only two resides in helix 7 line the LBD: Phe-349 and Ile-353
hydrophobic residues of helix 11 are Val-439,
Of helix 12,
Leu-453 and Trp-457 line the LBD.
is located in a
three stranded beta sheet and it also
contributes hydrophobicity to the ligand binding domain.
entrance to the
helix five and the loop
between β strands S1 and S2.
helix helps stabilize the LBD. This
helix assists in
binding through hydrophobic contacts between Trp-457
of helix 11
essential for the activation of the receptor in LXR beta.
Ligand Binding eCH
called eCH, is shown bound in the ligand
eCH consists of a four ring
steroid core, a phenolic hydroxyl, a sterol chain, and an epoxide
here to view ligands The
interaction crucial to ligand binding occurs between the epoxide
involves a hydrogen
the epoxide oxygen
and the imidazole
similar interaction also
occurs between His-435 and the acidic carbonyl groups of synthetic
occurs between the A-ring phenolic hydroxyl
and the Glu-281
Activation: Histadine-Tryptophan Switch
the ligand is bound to His-435, this residue is oriented
in a unique interaction with the active site. In this instance, His-435
interacting with Trp-457
on the inner surface of the AF2
in which the planar face of Trp-457 is oriented towards the edge of
orientation puts the AF-2
helix in the "activated"
conformation so that AF-2
can interact with
orientation, histadine exhibits
rotational freedom that allows it to "swing" across the face of the
and interact with the strongly
pi electron cloud of the
residue or the weakly
negative electron cloud
associated with the five
conserved in ligand activation by all other known LXR ligands. The
activation of LXR by different ligands is
partially due to the ability of His-435
to act as a hydrogen donor
in the activated
conformation, the AF-2 helix facilitates TIF-2 binding.
is a coactivator transcription initiation
factor. The binding of the cofactor facilitates transcription.
S, Schmid A, Heckel A, Budzinski RM, Nar H. (2003). Crystal structure
human liver X receptor beta ligand-binding domain in complex with a
agonist. Journal of Molecular
Biology, 334, 853-861.
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lipogenic enzyme gene transcription Proceedings
of the National
Sciences, 101(44), 15597-15602.
S. A. (1997). Activation of the nuclear receptor LXR by oxysterols
new hormone response pathway Journal
of Biological Chemistry, 272(6),
3137 - 3140.
X receptor ß (NR1H2) | NRResource.org Retrieved
S., Bledsoe, R.K., Collins, J.L., Boggs, S., Lambert, M.H., Miller,
Moore, J., McKee, D.D., Moore, L., Nichols, J., Parks, D., Watson, M.,
B., Willson, T.M. (2003). X-ray crystal structure of the liver X
ligand binding domain. The
Journal of Biological Chemistry, 278(July