Target Information
| Target General Information | Top | |||||
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| Target ID |
T52297
(Former ID: TTDR00420)
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| Target Name |
Oxysterols receptor LXR-alpha (NR1H3)
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| 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
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| Target Type |
Patented-recorded target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | 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.
Click to Show/Hide
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| BioChemical Class |
Nuclear hormone receptor
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| UniProt ID | ||||||
| Sequence |
MSLWLGAPVPDIPPDSAVELWKPGAQDASSQAQGGSSCILREEARMPHSAGGTAGVGLEA
AEPTALLTRAEPPSEPTEIRPQKRKKGPAPKMLGNELCSVCGDKASGFHYNVLSCEGCKG FFRRSVIKGAHYICHSGGHCPMDTYMRRKCQECRLRKCRQAGMREECVLSEEQIRLKKLK RQEEEQAHATSLPPRASSPPQILPQLSPEQLGMIEKLVAAQQQCNRRSFSDRLRVTPWPM APDPHSREARQQRFAHFTELAIVSVQEIVDFAKQLPGFLQLSREDQIALLKTSAIEVMLL ETSRRYNPGSESITFLKDFSYNREDFAKAGLQVEFINPIFEFSRAMNELQLNDAEFALLI AISIFSADRPNVQDQLQVERLQHTYVEALHAYVSIHHPHDRLMFPRMLMKLVSLRTLSSV HSEQVFALRLQDKKLPPLLSEIWDVHE Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| HIT2.0 ID | T57L0X | |||||
| Chemical Structure based Activity Landscape of Target | Top |
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| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "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 | |||||
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| Target Poor or Non Binders | ||||||
| Target Regulators | Top | |||||
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| Target-regulating microRNAs | ||||||
| Target-interacting Proteins | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 3 KEGG Pathways | + | ||||
| 1 | PPAR signaling pathway | |||||
| 2 | Non-alcoholic fatty liver disease (NAFLD) | |||||
| 3 | Hepatitis C | |||||
| PID Pathway | [+] 1 PID Pathways | + | ||||
| 1 | RXR and RAR heterodimerization with other nuclear receptor | |||||
| WikiPathways | [+] 7 WikiPathways | + | ||||
| 1 | Nuclear Receptors in Lipid Metabolism and Toxicity | |||||
| 2 | Nuclear Receptors Meta-Pathway | |||||
| 3 | PPAR Alpha Pathway | |||||
| 4 | Liver X Receptor Pathway | |||||
| 5 | Adipogenesis | |||||
| 6 | SREBF and miR33 in cholesterol and lipid homeostasis | |||||
| 7 | Nuclear Receptors | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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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. | |||||
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