Target Information
| Target General Information | Top | |||||
|---|---|---|---|---|---|---|
| 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
Click to Show/Hide
|
|||||
| Gene Name |
NR1H2
|
|||||
| Target Type |
Clinical trial target
|
[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | 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.
Click to Show/Hide
|
|||||
| BioChemical Class |
Nuclear hormone receptor
|
|||||
| UniProt ID | ||||||
| Sequence |
MSSPTTSSLDTPLPGNGPPQPGAPSSSPTVKEEGPEPWPGGPDPDVPGTDEASSACSTDW
VIPDPEEEPERKRKKGPAPKMLGHELCRVCGDKASGFHYNVLSCEGCKGFFRRSVVRGGA RRYACRGGGTCQMDAFMRRKCQQCRLRKCKEAGMREQCVLSEEQIRKKKIRKQQQESQSQ SQSPVGPQGSSSSASGPGASPGGSEAGSQGSGEGEGVQLTAAQELMIQQLVAAQLQCNKR SFSDQPKVTPWPLGADPQSRDARQQRFAHFTELAIISVQEIVDFAKQVPGFLQLGREDQI ALLKASTIEIMLLETARRYNHETECITFLKDFTYSKDDFHRAGLQVEFINPIFEFSRAMR RLGLDDAEYALLIAINIFSADRPNVQEPGRVEALQQPYVEALLSYTRIKRPQDQLRFPRM LMKLVSLRTLSSVHSEQVFALRLQDKKLPPLLSEIWDVHE Click to Show/Hide
|
|||||
| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| HIT2.0 ID | T34Y8V | |||||
| Drugs and Modes of Action | Top | |||||
|---|---|---|---|---|---|---|
| Clinical Trial Drug(s) | [+] 1 Clinical Trial Drugs | + | ||||
| 1 | VTB-38543 | Drug Info | Phase 2 | Atopic dermatitis | [1] | |
| Mode of Action | [+] 3 Modes of Action | + | ||||
| Agonist | [+] 9 Agonist drugs | + | ||||
| 1 | VTB-38543 | Drug Info | [1] | |||
| 2 | 22R-hydroxycholesterol | Drug Info | [4] | |||
| 3 | 24(S), 25-epoxycholesterol | Drug Info | [5] | |||
| 4 | 24(S)-hydroxycholesterol | Drug Info | [6] | |||
| 5 | 27-hydroxycholesterol | Drug Info | [7] | |||
| 6 | acetyl-podocarpic dimer | Drug Info | [8] | |||
| 7 | AZ12260493 | Drug Info | [9] | |||
| 8 | desmosterol | Drug Info | [11] | |||
| 9 | L-783483 | Drug Info | [14] | |||
| Inhibitor | [+] 11 Inhibitor drugs | + | ||||
| 1 | 12,17-dehydroxyriccardin C | Drug Info | [2] | |||
| 2 | 12-dehydroxyriccardin C | Drug Info | [2] | |||
| 3 | 2-benzyl-4,5,6,7-tetrachloroisoindoline-1,3-dione | Drug Info | [3] | |||
| 4 | 4,17-dehydroxyriccardin C | Drug Info | [2] | |||
| 5 | 4-dehydroxyriccardin C | Drug Info | [2] | |||
| 6 | Benzenesulfonyl | Drug Info | [10] | |||
| 7 | GSK-9772 | Drug Info | [12] | |||
| 8 | GW-3965 | Drug Info | [13] | |||
| 9 | N-{4-[2-(3-Methoxyphenyl)ethyl]phenyl}phthalimide | Drug Info | [15] | |||
| 10 | Riccardin C | Drug Info | [2] | |||
| 11 | WAY-254011 | Drug Info | [17] | |||
| Antagonist | [+] 1 Antagonist drugs | + | ||||
| 1 | SR9238 | Drug Info | [16] | |||
| Cell-based Target Expression Variations | Top | |||||
|---|---|---|---|---|---|---|
| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
|---|---|---|---|---|---|---|
| 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 | No | [18] |
| PDB Sequence |
VQLTAAQELM
227 IQQLVAAQLQ237 CNKRSFSDQP247 KVTPWPLGAD257 PQSRDARQQR267 FAHFTELAII 277 SVQEIVDFAK287 QVPGFLQLGR297 EDQIALLKAS307 TIEIMLLETA317 RRYNHETECI 327 TFLKDFTYSK337 DDFHRAGLQV347 EFINPIFEFS357 RAMRRLGLDD367 AEYALLIAIN 377 IFSADRPNVQ387 EPGRVEALQQ397 PYVEALLSYT407 RIKRPQDQLR417 FPRMLMKLVS 427 LRTLSSVHSE437 QVFALRKLPP451 LLSEIW
|
|||||
|
|
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
|
|||||
| 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 | No | [19] |
| PDB Sequence |
QLTAAQELMI
228 QQLVAAQLQC238 NKRPKVTPWP253 RDARQQRFAH270 FTELAIISVQ280 EIVDFAKQVP 290 GFLQLGREDQ300 IALLKASTIE310 IMLLETARRY320 NHETECITFL330 KDFTYSKDDF 340 HRAGLQVEFI350 NPIFEFSRAM360 RRLGLDDAEY370 ALLIAINIFS380 ADRPNVQEPG 390 RVEALQQPYV400 EALLSYTRIK410 RPQDQLRFPR420 MLMKLVSLRT430 LSSVHSEQVF 440 ALRLQDKKLP450 PLLSEIWD
|
|||||
|
|
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
|
|||||
| 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
|
|
|
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 | Top |
|---|---|
| Drug Property Profile of Target | Top | |
|---|---|---|
| (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 | Top | |||||
|---|---|---|---|---|---|---|
| Target Poor or Non Binders | ||||||
| Target Regulators | Top | |||||
|---|---|---|---|---|---|---|
| Target-interacting Proteins | ||||||
| Target Affiliated Biological Pathways | Top | |||||
|---|---|---|---|---|---|---|
| PID Pathway | [+] 1 PID Pathways | + | ||||
| 1 | RXR and RAR heterodimerization with other nuclear receptor | |||||
| Reactome | [+] 1 Reactome Pathways | + | ||||
| 1 | Nuclear Receptor transcription pathway | |||||
| WikiPathways | [+] 2 WikiPathways | + | ||||
| 1 | SREBP signalling | |||||
| 2 | Nuclear Receptors | |||||
| Target-Related Models and Studies | Top | |||||
|---|---|---|---|---|---|---|
| Target Validation | ||||||
| References | Top | |||||
|---|---|---|---|---|---|---|
| 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 | 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 4 | An oxysterol signalling pathway mediated by the nuclear receptor LXR alpha. Nature. 1996 Oct 24;383(6602):728-31. | |||||
| REF 5 | Brain endogenous liver X receptor ligands selectively promote midbrain neurogenesis. Nat Chem Biol. 2013 Feb;9(2):126-33. | |||||
| REF 6 | 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 7 | 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 8 | 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 9 | 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 10 | How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6. | |||||
| REF 11 | Sterol intermediates from cholesterol biosynthetic pathway as liver X receptor ligands. J Biol Chem. 2006 Sep 22;281(38):27816-26. | |||||
| REF 12 | 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 13 | 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 14 | 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 15 | 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 16 | A liver-selective LXR inverse agonist that suppresses hepatic steatosis. ACS Chem Biol. 2013 Mar 15;8(3):559-67. | |||||
| REF 17 | 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 18 | 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 19 | Discovery of Highly Potent Liver X Receptor beta Agonists. ACS Med Chem Lett. 2016 Oct 23;7(12):1207-1212. | |||||
If You Find Any Error in Data or Bug in Web Service, Please Kindly Report It to Dr. Zhou and Dr. Zhang.