Homo sapien
Liver
X Receptor Beta
Kelly Heilman '12 and Crystal Piras '12
Contents:
I.
Introduction
Liver
X receptors are ligand
activated transcription factors that are part of the protein family on
nuclear
receptors.
Nuclear receptors
regulate transcription
intracellularly
mainly through recruitment of coactivators. Liver X receptors are
activated by
oxysterol ligands, also called oxygenated cholesterol
metabolites.
These
LXR's are involved in the regulation of
cholesterol, and therefore are of interest in treating cardiovascular
diseases
such as atherosclerosis.
More specifically,
LXRα and LXR
β regulate
lipogenesis in the liver through LXR
target genes
including ChREBP (carbohydrate response element binding protein) and
SREBP1c
(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
unwanted
hepatic side effects.
Several
known LXR ligands include the
endogenous ligand 24(S),25-epoxycholesterol (eCH) and synthetic
agonists T1317
and GW3965 (both non-sterol).
II.
General Structure
Typical
of nuclear receptors,
liver X receptor β has three layers of alpha helices.
The
asymmetric
unit of this crystal consists of an LXR homodimer complexed
with its coactivator SRC-1.
Each
LXR
monomer is characterized by 10 total helices
and the AF2
Helix. The
AF2 helix interacts with the ligand binding pocket as well as the
transcription cofactor SRC-1 and is a domain common to Nuclear
Receptors.
Helices
7,
9,
and 10
make up the dimer interface.
Other
characteristic
features of the LXR β include a long helix 1,
which
is made up of about 18 amino acid residues.
LXR
β has a large ligand
binding pocket that is 830 Å3.
III.
Ligand Binding Pocket
LXR
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
associated with
cardiovascular disease from being transcribed. The ligand binding
domain
is a large
cavity
made
up of three layers of alpha helices: Helices
3, 5, 6, 7,
11, and 12.
The
LBD is
completely lined with hydrophobic residues except for His-435 located in helix 11.
The
hydrophobic residues of helix 3 are Phe-268,
Phe-271,
Thr-272, Leu-274, Ala-275.
Of
helix 5 Ile-309,
Met-312,
Leu-313, and
Thr-316
line the LBD.
Helix
6 contributes to the LBD but it does not contribute any amino acid
residues to
the lining of the cavity. Only two resides in helix 7 line the LBD: Phe-349 and Ile-353
The
hydrophobic residues of helix 11 are Val-439,
and
Leu-442.
Of helix 12,
Leu-453 and Trp-457 line the LBD.
Ile-327
is located in a
small
three stranded beta sheet and it also
contributes hydrophobicity to the ligand binding domain.
The
entrance to the
LBD is
located
between
helix five and the loop
between β strands S1 and S2.
The
AF2
helix helps stabilize the LBD. This
helix assists in
binding through hydrophobic contacts between Trp-457
and His-435
of helix 11
and is
essential for the activation of the receptor in LXR beta.
IV.
Ligand Binding eCH
An endogenous
oxysterol ligand,
24(S),25-epoxycholesterol,
called eCH, is shown bound in the ligand
binding
domain.
eCH consists of a four ring
steroid core, a phenolic hydroxyl, a sterol chain, and an epoxide
oxygen. click
here to view ligands The
main
interaction crucial to ligand binding occurs between the epoxide
oxygen
and His-435.
This
interaction
involves a hydrogen
bond
between
the epoxide oxygen
and the imidazole
ring of
His-435.
A
similar interaction also
occurs between His-435 and the acidic carbonyl groups of synthetic
ligands that
also can
bind
LXR.
Another interaction
occurs between the A-ring phenolic hydroxyl
group
and the Glu-281
located on
helix 3.
V.
Ligand
Activation: Histadine-Tryptophan Switch
When
the ligand is bound to His-435, this residue is oriented
in a unique interaction with the active site. In this instance, His-435
orthogonally
interacting with Trp-457
on the inner surface of the AF2
helix,
in which the planar face of Trp-457 is oriented towards the edge of
His-435.
This
face-to-edge
orientation puts the AF-2
helix in the "activated"
conformation so that AF-2
can interact with
the SRC-1
cofactor.
In
this
orientation, histadine exhibits
rotational freedom that allows it to "swing" across the face of the
tryptophan
and interact with the strongly
negative
pi electron cloud of the
benzene
residue or the weakly
negative electron cloud
associated with the five
membered
ring residue.
This
interaction is
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
and
an acceptor.
Once
in the activated
conformation, the AF-2 helix facilitates TIF-2 binding.
TIF-2
is a coactivator transcription initiation
factor. The binding of the cofactor facilitates transcription.
VI.
References
Hoerer
S, Schmid A, Heckel A, Budzinski RM, Nar H. (2003). Crystal structure
of the
human liver X receptor beta ligand-binding domain in complex with a
synthetic
agonist. Journal of Molecular
Biology, 334, 853-861.
Ishii,
S. (2004). Carbohydrate response element binding protein directly
promotes
lipogenic enzyme gene transcription Proceedings
of the National
Academy of
Sciences, 101(44), 15597-15602.
Kliewer,
S. A. (1997). Activation of the nuclear receptor LXR by oxysterols
defines a
new hormone response pathway Journal
of Biological Chemistry, 272(6),
3137 - 3140.
Liver
X receptor ß (NR1H2) | NRResource.org Retrieved
12/6/2010, 2010,
from http://nrresource.org/nr_page_collection/liver_x_receptor_beta_nr1h2.html
Williams,
S., Bledsoe, R.K., Collins, J.L., Boggs, S., Lambert, M.H., Miller,
A.B.,
Moore, J., McKee, D.D., Moore, L., Nichols, J., Parks, D., Watson, M.,
Wisely,
B., Willson, T.M. (2003). X-ray crystal structure of the liver X
receptor β
ligand binding domain. The
Journal of Biological Chemistry, 278(July
18), 27138-27143.
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