Target Information

Target General Information

Target ID

T52297 (Former ID: TTDR00420)

Target Name

Oxysterols receptor LXR-alpha (NR1H3)

Synonyms

Nuclear receptor subfamily 1 group H member 3; Nuclear receptor LXRalpha; Nuclear orphan receptor LXR-alpha; Liver X receptor alpha; LXRalpha; LXRA

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Gene Name

NR1H3

Target Type

Patented-recorded target

[1]

Disease

[+] 1 Target-related Diseases

Depression [ICD-11: 6A70-6A7Z]

Function

Interaction with retinoic acid receptor (RXR) shifts RXR from its role as a silent DNA-binding partner to an active ligand-binding subunit in mediating retinoid responses through target genes defined by LXRES. LXRES are DR4-type response elements characterized by direct repeats of two similar hexanuclotide half-sites spaced by four nucleotides. Plays an important role in the regulation of cholesterol homeostasis, regulating cholesterol uptake through MYLIP-dependent ubiquitination of LDLR, VLDLR and LRP8. Interplays functionally with RORA for the regulation of genes involved in liver metabolism. Nuclear receptor that exhibits a ligand-dependent transcriptional activation activity.

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BioChemical Class

Nuclear hormone receptor

UniProt ID

NR1H3_HUMAN

Sequence

MSLWLGAPVPDIPPDSAVELWKPGAQDASSQAQGGSSCILREEARMPHSAGGTAGVGLEA
AEPTALLTRAEPPSEPTEIRPQKRKKGPAPKMLGNELCSVCGDKASGFHYNVLSCEGCKG
FFRRSVIKGAHYICHSGGHCPMDTYMRRKCQECRLRKCRQAGMREECVLSEEQIRLKKLK
RQEEEQAHATSLPPRASSPPQILPQLSPEQLGMIEKLVAAQQQCNRRSFSDRLRVTPWPM
APDPHSREARQQRFAHFTELAIVSVQEIVDFAKQLPGFLQLSREDQIALLKTSAIEVMLL
ETSRRYNPGSESITFLKDFSYNREDFAKAGLQVEFINPIFEFSRAMNELQLNDAEFALLI
AISIFSADRPNVQDQLQVERLQHTYVEALHAYVSIHHPHDRLMFPRMLMKLVSLRTLSSV
HSEQVFALRLQDKKLPPLLSEIWDVHE

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3D Structure

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AlphaFold

HIT2.0 ID

T57L0X

Cell-based Target Expression Variations

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Cell-based Target Expression Variations

Cell-based Target Expression Variations Info

Drug Binding Sites of Target

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Ligand Name: GW-3965

Ligand Info

Structure Description

X-ray structure of GW3965 synthetic agonist bound to the LXR-alpha

PDB:3IPQ

Method

X-ray diffraction

Resolution

2.00 Å

Mutation

[22]

PDB Sequence

QLSPEQLGMI

²¹⁴

EKLVAAQQTP

²³⁷

WPEARQQRFA

²⁵⁵

HFTELAIVSV

²⁶⁵

QEIVDFAKQL

²⁷⁵

PGFLQLSRED

²⁸⁵

QIALLKTSAI

²⁹⁵

EVMLLETSRR

³⁰⁵

YNPGSESITF

³¹⁵

LKDFSYNRED

³²⁵

FAKAGLQVEF

³³⁵

INPIFEFSRA

³⁴⁵

MNELQLNDAE

³⁵⁵

FALLIAISIF

³⁶⁵

SADRPNVQDQ

³⁷⁵

LQVERLQHTY

³⁸⁵

VEALHAYVSI

³⁹⁵

HHPHDRLMFP

⁴⁰⁵

RMLMKLVSLR

⁴¹⁵

TLSSVHSEQV

⁴²⁵

FALRLQDKKL

⁴³⁵

PPLLSEIWDV

⁴⁴⁵

Residue

Distance (Å)

PHE254

4.197

PHE257

3.554

THR258

3.873

LEU260

3.396

ALA261

3.613

VAL263

4.494

SER264

3.573

GLU267

3.762

ILE295

3.747

MET298

3.559

LEU299

3.623

GLU301

4.050

THR302

3.151

ARG305

2.857

ILE313

3.754

THR314

4.348

Residue

Distance (Å)

PHE315

3.359

LEU316

2.872

PHE326

3.661

LEU331

3.871

PHE335

3.582

ILE336

3.727

ILE339

3.409

PHE340

3.733

HIS421

3.652

GLN424

3.677

VAL425

3.823

LEU428

3.651

LEU435

3.279

LEU439

4.943

TRP443

3.472

Ligand Name: L-783483

Ligand Info

Structure Description

X-ray structure of benzisoxazole synthetic agonist bound to the LXR-alpha

PDB:3IPS

Method

X-ray diffraction

Resolution

2.26 Å

Mutation

[22]

PDB Sequence

QLSPEQLGMI

²¹⁴

EKLVAAQQVT

²³⁶

PWPSREARQQ

²⁵²

RFAHFTELAI

²⁶²

VSVQEIVDFA

²⁷²

KQLPGFLQLS

²⁸²

REDQIALLKT

²⁹²

SAIEVMLLET

³⁰²

SRRYNPGSES

³¹²

ITFLKDFSYN

³²²

REDFAKAGLQ

³³²

VEFINPIFEF

³⁴²

SRAMNELQLN

³⁵²

DAEFALLIAI

³⁶²

SIFSADRPNV

³⁷²

QDQLQVERLQ

³⁸²

HTYVEALHAY

³⁹²

VSIHHPHDRL

⁴⁰²

MFPRMLMKLV

⁴¹²

SLRTLSSVHS

⁴²²

EQVFALRLQD

⁴³²

KKLPPLLSEI

⁴⁴²

WDVH

Residue

Distance (Å)

PHE254

4.177

PHE257

3.307

THR258

3.810

LEU260

2.958

ALA261

3.861

VAL263

4.808

SER264

3.776

GLU267

4.245

ILE295

4.142

MET298

3.345

LEU299

3.986

GLU301

3.320

THR302

3.320

ARG305

2.829

Residue

Distance (Å)

PHE315

3.377

LEU316

3.810

PHE326

4.493

LEU331

4.220

PHE335

3.123

ILE339

4.411

HIS421

3.438

GLN424

3.592

VAL425

4.025

LEU428

3.417

LEU435

3.478

LEU439

4.752

TRP443

2.925

Click to View More Binding Site Information of This Target with Different Ligands

Different Human System Profiles of Target	Top
Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target. A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020). Human Tissue Distribution of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues. The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects (Nat Rev Drug Discov, 20: 64-81, 2021). Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function. Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006). Biological Network Descriptors of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database. The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information (Front Pharmacol, 9, 1245, 2018; Curr Opin Struct Biol. 44:134-142, 2017). Human Similarity Proteins Human Tissue Distribution Human Pathway Affiliation Biological Network Descriptors

Different Human System Profiles of Target

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Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.

A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020).

Human Tissue Distribution of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.

The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects (Nat Rev Drug Discov, 20: 64-81, 2021).

Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.

Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006).

Biological Network Descriptors of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.

The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information (Front Pharmacol, 9, 1245, 2018; Curr Opin Struct Biol. 44:134-142, 2017).

Human Similarity Proteins

Human Tissue Distribution

Human Pathway Affiliation

Biological Network Descriptors

There is no similarity protein (E value < 0.005) for this target


Note: If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.

KEGG Pathway	Pathway ID	Affiliated Target	Pathway Map
PPAR signaling pathway	hsa03320	Affiliated Target
Class: Organismal Systems => Endocrine system	Pathway Hierarchy

Degree	21	Degree centrality	2.26E-03	Betweenness centrality	1.71E-03
Closeness centrality	2.32E-01	Radiality	1.41E+01	Clustering coefficient	1.76E-01
Neighborhood connectivity	2.75E+01	Topological coefficient	7.92E-02	Eccentricity	11
Download	Click to Download the Full PPI Network of This Target

Chemical Structure based Activity Landscape of Target

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Drug Property Profile of Target

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(1) Molecular Weight (mw) based Drug Clustering

(2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering

(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering

(4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering

(5) Rotatable Bond Count (rotbonds) based Drug Clustering

(6) Topological Polar Surface Area (polararea) based Drug Clustering

"RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five

Target Poor or Non Binders

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Target Poor or Non Binders

Target Poor or Non Binders Info

Target Regulators

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Target-regulating microRNAs

Target-regulating microRNAs Info

Target-interacting Proteins

Target-interacting Proteins Info

Target Affiliated Biological Pathways

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KEGG Pathway

[+] 3 KEGG Pathways

PPAR signaling pathway

Non-alcoholic fatty liver disease (NAFLD)

Hepatitis C

PID Pathway

[+] 1 PID Pathways

RXR and RAR heterodimerization with other nuclear receptor

WikiPathways

[+] 7 WikiPathways

Nuclear Receptors in Lipid Metabolism and Toxicity

Nuclear Receptors Meta-Pathway

PPAR Alpha Pathway

Liver X Receptor Pathway

Adipogenesis

SREBF and miR33 in cholesterol and lipid homeostasis

Nuclear Receptors

Target-Related Models and Studies

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Target Validation

Target Validation Info

References

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REF 1

A liver-selective LXR inverse agonist that suppresses hepatic steatosis. ACS Chem Biol. 2013 Mar 15;8(3):559-67.

REF 2

Piperazine derivatives as liver X receptor modulators. US10144715.

REF 3

Liver X receptor modulators. US9006244.

REF 4

Liver X receptor modulators. US9073931.

REF 5

Co-existence of alpha-glucosidase-inhibitory and liver X receptor-regulatory activities and their separation by structural development. Bioorg Med Chem. 2008 Apr 15;16(8):4272-85.

REF 6

Separation of alpha-glucosidase-inhibitory and liver X receptor-antagonistic activities of phenethylphenyl phthalimide analogs and generation of LX... Bioorg Med Chem. 2009 Jul 15;17(14):5001-14.

REF 7

Indazole-based liver X receptor (LXR) modulators with maintained atherosclerotic lesion reduction activity but diminished stimulation of hepatic tr... J Med Chem. 2008 Nov 27;51(22):7161-8.

REF 8

Liver X receptor antagonists with a phthalimide skeleton derived from thalidomide-related glucosidase inhibitors. Bioorg Med Chem Lett. 2007 Jul 15;17(14):3957-61.

REF 9

An oxysterol signalling pathway mediated by the nuclear receptor LXR alpha. Nature. 1996 Oct 24;383(6602):728-31.

REF 10

Brain endogenous liver X receptor ligands selectively promote midbrain neurogenesis. Nat Chem Biol. 2013 Feb;9(2):126-33.

REF 11

Activation of the nuclear receptor LXR by oxysterols defines a new hormone response pathway. J Biol Chem. 1997 Feb 7;272(6):3137-40.

REF 12

27-hydroxycholesterol is an endogenous ligand for liver X receptor in cholesterol-loaded cells. J Biol Chem. 2001 Oct 19;276(42):38378-87.

REF 13

A potent synthetic LXR agonist is more effective than cholesterol loading at inducing ABCA1 mRNA and stimulating cholesterol efflux. J Biol Chem. 2002 Mar 22;277(12):10021-7.

REF 14

URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 602).

REF 15

Sterol intermediates from cholesterol biosynthetic pathway as liver X receptor ligands. J Biol Chem. 2006 Sep 22;281(38):27816-26.

REF 16

Structure-guided design of N-phenyl tertiary amines as transrepression-selective liver X receptor modulators with anti-inflammatory activity. J Med Chem. 2008 Sep 25;51(18):5758-65.

REF 17

Discovery of tertiary sulfonamides as potent liver X receptor antagonists. J Med Chem. 2010 Apr 22;53(8):3412-6.

REF 18

Guttiferone I, a new prenylated benzophenone from Garcinia humilis as a liver X receptor ligand. J Nat Prod. 2005 Apr;68(4):617-9.

REF 19

A novel liver X receptor agonist establishes species differences in the regulation of cholesterol 7alpha-hydroxylase (CYP7a). Endocrinology. 2002 Jul;143(7):2548-58.

REF 20

A natural product ligand of the oxysterol receptor, liver X receptor. J Pharmacol Exp Ther. 2003 Oct;307(1):291-6.

REF 21

Discovery and SAR of cinnolines/quinolines as liver X receptor (LXR) agonists with binding selectivity for LXRbeta. Bioorg Med Chem. 2009 May 15;17(10):3519-27.

REF 22

X-ray structures of the LXRalpha LBD in its homodimeric form and implications for heterodimer signaling. J Mol Biol. 2010 May 28;399(1):120-32.

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