Target Information
| Target General Information | Top | |||||
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| Target ID |
T82702
(Former ID: TTDR01273)
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| Target Name |
Pregnane X receptor (NR1I2)
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| Synonyms |
Steroid and xenobiotic receptor; SXR; PXR; Orphan nuclear receptor PXR; Orphan nuclear receptor PAR1; Nuclear receptor subfamily 1 group I member 2
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| Gene Name |
NR1I2
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| Target Type |
Literature-reported target
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[1] | ||||
| Function |
Transcription factor that activates the transcription of multiple genes involved in the metabolism and secretion of potentially harmful xenobiotics, drugs and endogenous compounds. Activated by the antibiotic rifampicin and various plant metabolites, such as hyperforin, guggulipid, colupulone, and isoflavones. Response to specific ligands is species-specific. Activated by naturally occurring steroids, such as pregnenolone and progesterone. Binds to a response element in the promoters of the CYP3A4 and ABCB1/MDR1 genes. Nuclear receptor that binds and is activated by variety of endogenous and xenobiotic compounds.
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| BioChemical Class |
Nuclear hormone receptor
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| UniProt ID | ||||||
| Sequence |
MEVRPKESWNHADFVHCEDTESVPGKPSVNADEEVGGPQICRVCGDKATGYHFNVMTCEG
CKGFFRRAMKRNARLRCPFRKGACEITRKTRRQCQACRLRKCLESGMKKEMIMSDEAVEE RRALIKRKKSERTGTQPLGVQGLTEEQRMMIRELMDAQMKTFDTTFSHFKNFRLPGVLSS GCELPESLQAPSREEAAKWSQVRKDLCSLKVSLQLRGEDGSVWNYKPPADSGGKEIFSLL PHMADMSTYMFKGIISFAKVISYFRDLPIEDQISLLKGAAFELCQLRFNTVFNAETGTWE CGRLSYCLEDTAGGFQQLLLEPMLKFHYMLKKLQLHEEEYVLMQAISLFSPDRPGVLQHR VVDQLQEQFAITLKSYIECNRPQPAHRFLFLKIMAMLTELRSINAQHTQRLLRIQDIHPF ATPLMQELFGITGS Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| HIT2.0 ID | T50SX0 | |||||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: Clotrimazole | Ligand Info | |||||
| Structure Description | Crystal structure of the hPXR-LBD in complex with clotrimazole | PDB:7AXA | ||||
| Method | X-ray diffraction | Resolution | 2.26 Å | Mutation | No | [7] |
| PDB Sequence |
GLTEEQRMMI
151 RELMDAQMKT161 FDTTFSHFKN171 FRLPGVEAAK198 WSQVRKDLCS208 LKVSLQLRGE 218 DGSVWNYKPP228 ADSGGKEIFS238 LLPHMADMST248 YMFKGIISFA258 KVISYFRDLP 268 IEDQISLLKG278 AAFELCQLRF288 NTVFNAETGT298 WECGRLSYCL308 EDQQLLLEPM 323 LKFHYMLKKL333 QLHEEEYVLM343 QAISLFSPDR353 PGVLQHRVVD363 QLQEQFAITL 373 KSYIECNRPQ383 PAHRFLFLKI393 MAMLTELRSI403 NAQHTQRLLR413 IQDIHPFATP 423 LMQELFGITG433 SL
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Ligand Name: Estradiol | Ligand Info | |||||
| Structure Description | Crystal structure of the hPXR-LBD in complex with estradiol and endosulfan | PDB:7AXK | ||||
| Method | X-ray diffraction | Resolution | 2.00 Å | Mutation | No | [7] |
| PDB Sequence |
GLTEEQRMMI
151 RELMDAQMKT161 FDTTFSHFKN171 FRLPGVEAAK198 WSQVRKDLCS208 LKVSLQLRGE 218 DGSVWNYKPP228 ADSGGKEIFS238 LLPHMADMST248 YMFKGIISFA258 KVISYFRDLP 268 IEDQISLLKG278 AAFELCQLRF288 NTVFNAETGT298 WECGRLSYCL308 EDFQQLLLEP 322 MLKFHYMLKK332 LQLHEEEYVL342 MQAISLFSPD352 RPGVLQHRVV362 DQLQEQFAIT 372 LKSYIECNRP382 QPAHRFLFLK392 IMAMLTELRS402 INAQHTQRLL412 RIQDIHPFAT 422 PLMQELFGIT432 GS
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| Different Human System Profiles of Target | Top |
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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).
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
Biological Network Descriptors
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There is no similarity protein (E value < 0.005) for this target
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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.
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| Degree | 5 | Degree centrality | 5.37E-04 | Betweenness centrality | 1.94E-07 |
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| Closeness centrality | 2.13E-01 | Radiality | 1.37E+01 | Clustering coefficient | 8.00E-01 |
| Neighborhood connectivity | 4.10E+01 | Topological coefficient | 3.45E-01 | Eccentricity | 11 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| 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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| WikiPathways | [+] 5 WikiPathways | + | ||||
| 1 | Nuclear Receptors in Lipid Metabolism and Toxicity | |||||
| 2 | Nuclear Receptors Meta-Pathway | |||||
| 3 | Pregnane X Receptor pathway | |||||
| 4 | Drug Induction of Bile Acid Pathway | |||||
| 5 | Nuclear Receptors | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | Traditional Chinese medicines Wu Wei Zi (Schisandra chinensis Baill) and Gan Cao (Glycyrrhiza uralensis Fisch) activate pregnane X receptor and inc... J Pharmacol Exp Ther. 2006 Mar;316(3):1369-77. | |||||
| REF 2 | The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity. Proc Natl Acad Sci U S A. 2001 Mar 13;98(6):3369-74. | |||||
| REF 3 | Pregnane X receptor (PXR) regulates P-glycoprotein at the blood-brain barrier: functional similarities between pig and human PXR. J Pharmacol Exp Ther. 2009 Apr;329(1):141-9. | |||||
| REF 4 | An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathway. Cell. 1998 Jan 9;92(1):73-82. | |||||
| REF 5 | Identification of bile acid precursors as endogenous ligands for the nuclear xenobiotic pregnane X receptor. Proc Natl Acad Sci U S A. 2003 Jan 7;100(1):223-8. | |||||
| REF 6 | 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 7 | Mechanistic insights into the synergistic activation of the RXR-PXR heterodimer by endocrine disruptor mixtures. Proc Natl Acad Sci U S A. 2021 Jan 5;118(1):e2020551118. | |||||
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