Target Information

Target General Information

Target ID

T13714 (Former ID: TTDR00421)

Target Name

Oxysterols receptor LXR-beta (NR1H2)

Synonyms

Ubiquitously-expressed nuclear receptor; Nuclear receptor subfamily 1 group H member 2; Nuclear receptor NER; Nuclear orphan receptor LXR-beta; NER; Liver X receptor beta; LXRbeta; LXRB

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Gene Name

NR1H2

Target Type

Clinical trial target

[1]

Disease

[+] 1 Target-related Diseases

Atopic eczema [ICD-11: EA80]

Function

Binds preferentially to double-stranded oligonucleotide direct repeats having the consensus half-site sequence 5'-AGGTCA-3' and 4-nt spacing (DR-4). Regulates cholesterol uptake through MYLIP-dependent ubiquitination of LDLR, VLDLR and LRP8; DLDLR and LRP8. Interplays functionally with RORA for the regulation of genes involved in liver metabolism. Plays an anti-inflammatory role during the hepatic acute phase response by acting as a corepressor: inhibits the hepatic acute phase response by preventing dissociation of the N-Cor corepressor complex. Nuclear receptor that exhibits a ligand-dependent transcriptional activation activity.

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BioChemical Class

Nuclear hormone receptor

UniProt ID

NR1H2_HUMAN

Sequence

MSSPTTSSLDTPLPGNGPPQPGAPSSSPTVKEEGPEPWPGGPDPDVPGTDEASSACSTDW
VIPDPEEEPERKRKKGPAPKMLGHELCRVCGDKASGFHYNVLSCEGCKGFFRRSVVRGGA
RRYACRGGGTCQMDAFMRRKCQQCRLRKCKEAGMREQCVLSEEQIRKKKIRKQQQESQSQ
SQSPVGPQGSSSSASGPGASPGGSEAGSQGSGEGEGVQLTAAQELMIQQLVAAQLQCNKR
SFSDQPKVTPWPLGADPQSRDARQQRFAHFTELAIISVQEIVDFAKQVPGFLQLGREDQI
ALLKASTIEIMLLETARRYNHETECITFLKDFTYSKDDFHRAGLQVEFINPIFEFSRAMR
RLGLDDAEYALLIAINIFSADRPNVQEPGRVEALQQPYVEALLSYTRIKRPQDQLRFPRM
LMKLVSLRTLSSVHSEQVFALRLQDKKLPPLLSEIWDVHE

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3D Structure

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PDB

HIT2.0 ID

T34Y8V

Drugs and Modes of Action

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Clinical Trial Drug(s)

[+] 1 Clinical Trial Drugs

VTB-38543

Drug Info

Phase 2

Atopic dermatitis

[1]

Mode of Action

[+] 3 Modes of Action

Agonist

[+] 9 Agonist drugs

VTB-38543

Drug Info

[1]

22R-hydroxycholesterol

Drug Info

[6]

24(S), 25-epoxycholesterol

Drug Info

[7]

24(S)-hydroxycholesterol

Drug Info

[8]

27-hydroxycholesterol

Drug Info

[9]

acetyl-podocarpic dimer

Drug Info

[10]

AZ12260493

Drug Info

[11]

desmosterol

Drug Info

[12]

L-783483

Drug Info

[15]

Inhibitor

[+] 15 Inhibitor drugs

12,17-dehydroxyriccardin C

Drug Info

[2]

12-dehydroxyriccardin C

Drug Info

[2]

17-dehydroxyriccardin C

Drug Info

[2]

2-Benzyl-3-phenyl-7-(trifluoromethyl)-2H-indazole

Drug Info

[3]

2-benzyl-4,5,6,7-tetrachloroisoindoline-1,3-dione

Drug Info

[4]

2-Propanol, Isopropanol

Drug Info

[5]

4,17-dehydroxyriccardin C

Drug Info

[2]

4-dehydroxyriccardin C

Drug Info

[2]

Benzenesulfonyl

Drug Info

[5]

GSK-9772

Drug Info

[13]

GW-3965

Drug Info

[3]

N-{4-[2-(3-Methoxyphenyl)ethyl]phenyl}phthalimide

Drug Info

[16]

Riccardin C

Drug Info

[2]

WAY-214950

Drug Info

[3]

WAY-254011

Drug Info

[18]

Antagonist

[+] 2 Antagonist drugs

GSK2033

Drug Info

[14]

SR9238

Drug Info

[17]

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: BMS-779788

Ligand Info

Structure Description

Crystal structure of nuclear receptor subfamily 1, group h, member 2 (lxrb) complexed with partial agonist

PDB:4RAK

Method

X-ray diffraction

Resolution

2.04 Å

Mutation

[19]

PDB Sequence

VQLTAAQELM

²²⁷

IQQLVAAQLQ

²³⁷

CNKRSFSDQP

²⁴⁷

KVTPWPLGAD

²⁵⁷

PQSRDARQQR

²⁶⁷

FAHFTELAII

²⁷⁷

SVQEIVDFAK

²⁸⁷

QVPGFLQLGR

²⁹⁷

EDQIALLKAS

³⁰⁷

TIEIMLLETA

³¹⁷

RRYNHETECI

³²⁷

TFLKDFTYSK

³³⁷

DDFHRAGLQV

³⁴⁷

EFINPIFEFS

³⁵⁷

RAMRRLGLDD

³⁶⁷

AEYALLIAIN

³⁷⁷

IFSADRPNVQ

³⁸⁷

EPGRVEALQQ

³⁹⁷

PYVEALLSYT

⁴⁰⁷

RIKRPQDQLR

⁴¹⁷

FPRMLMKLVS

⁴²⁷

LRTLSSVHSE

⁴³⁷

QVFALRKLPP

⁴⁵¹

LLSEIW

Residue

Distance (Å)

SER242

4.902

PHE268

3.647

PHE271

3.634

THR272

3.336

LEU274

3.221

ALA275

3.429

ILE277

3.628

SER278

3.583

GLU281

3.371

ILE309

4.786

MET312

3.651

LEU313

3.532

Residue

Distance (Å)

GLU315

3.777

THR316

3.418

ARG319

2.939

THR328

4.904

PHE329

3.560

LEU330

2.730

PHE340

3.874

LEU345

3.689

PHE349

3.904

ILE353

3.670

HIS435

3.703

Ligand Name: BMS-852927

Ligand Info

Structure Description

CRYSTAL STRUCTURE OF LXRbeta (NUCLEAR RECEPTOR SUBFAMILY 1, GROUP H, MEMBER 2) COMPLEXED WITH BMS-852927

PDB:5JY3

Method

X-ray diffraction

Resolution

2.40 Å

Mutation

[20]

PDB Sequence

QLTAAQELMI

²²⁸

QQLVAAQLQC

²³⁸

NKRPKVTPWP

²⁵³

RDARQQRFAH

²⁷⁰

FTELAIISVQ

²⁸⁰

EIVDFAKQVP

²⁹⁰

GFLQLGREDQ

³⁰⁰

IALLKASTIE

³¹⁰

IMLLETARRY

³²⁰

NHETECITFL

³³⁰

KDFTYSKDDF

³⁴⁰

HRAGLQVEFI

³⁵⁰

NPIFEFSRAM

³⁶⁰

RRLGLDDAEY

³⁷⁰

ALLIAINIFS

³⁸⁰

ADRPNVQEPG

³⁹⁰

RVEALQQPYV

⁴⁰⁰

EALLSYTRIK

⁴¹⁰

RPQDQLRFPR

⁴²⁰

MLMKLVSLRT

⁴³⁰

LSSVHSEQVF

⁴⁴⁰

ALRLQDKKLP

⁴⁵⁰

PLLSEIWD

Residue

Distance (Å)

PHE268

3.926

PHE271

3.262

THR272

3.763

LEU274

2.993

ALA275

3.473

ILE277

3.768

SER278

3.475

GLU281

3.330

ILE309

4.370

ILE311

4.843

MET312

3.505

LEU313

4.214

Residue

Distance (Å)

GLU315

3.004

THR316

3.335

ARG319

3.025

PHE329

2.969

LEU330

3.135

PHE340

3.845

LEU345

3.618

PHE349

3.780

ILE350

4.344

ILE353

3.776

HIS435

4.202

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). 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 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).

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

Biological Network Descriptors

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

Degree	11	Degree centrality	1.18E-03	Betweenness centrality	1.14E-04
Closeness centrality	2.05E-01	Radiality	1.36E+01	Clustering coefficient	7.27E-02
Neighborhood connectivity	1.24E+01	Topological coefficient	1.29E-01	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-interacting Proteins

Target-interacting Proteins Info

Target Affiliated Biological Pathways

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PID Pathway

[+] 1 PID Pathways

RXR and RAR heterodimerization with other nuclear receptor

Reactome

[+] 1 Reactome Pathways

Nuclear Receptor transcription pathway

WikiPathways

[+] 2 WikiPathways

SREBP signalling

Nuclear Receptors

Target-Related Models and Studies

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Target Validation

Target Validation Info

References

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REF 1

Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)

REF 2

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 3

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 4

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 5

How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.

REF 6

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

REF 7

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

REF 8

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 9

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 10

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 11

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: 601).

REF 12

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

REF 13

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 14

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

REF 15

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 16

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 17

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

REF 18

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 19

Liver X receptor (LXR) partial agonists: biaryl pyrazoles and imidazoles displaying a preference for LXRbeta. Bioorg Med Chem Lett. 2015 Jan 15;25(2):372-7.

REF 20

Discovery of Highly Potent Liver X Receptor beta Agonists. ACS Med Chem Lett. 2016 Oct 23;7(12):1207-1212.

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