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Pregnane X receptor

From Wikipedia, the free encyclopedia
Mammalian protein found in Homo sapiens
"PXR" redirects here. For other uses, seePXR (disambiguation).
For file format .pxr, seePixar Image Computer,SXR, andsoft x-ray.
NR1I2
Available structures
PDBOrtholog search:PDBeRCSB
List of PDB id codes

1ILG,1ILH,1M13,1NRL,1SKX,2O9I,2QNV,3CTB,3HVL,3R8D,4J5W,4J5X,4NY9,4S0S,4S0T,4XHD,4X1F,4X1G,4XAO,5A86

Identifiers
AliasesNR1I2, BXR, ONR1, PAR, PAR1, PAR2, PARq, PRR, PXR, SAR, SXR, nuclear receptor subfamily 1 group I member 2
External IDsOMIM:603065;MGI:1337040;HomoloGene:40757;GeneCards:NR1I2;OMA:NR1I2 - orthologs
Gene location (Human)
Chromosome 3 (human)
Chr.Chromosome 3 (human)[1]
Chromosome 3 (human)
Genomic location for NR1I2
Genomic location for NR1I2
Band3q13.33Start119,780,484bp[1]
End119,818,487bp[1]
Gene location (Mouse)
Chromosome 16 (mouse)
Chr.Chromosome 16 (mouse)[2]
Chromosome 16 (mouse)
Genomic location for NR1I2
Genomic location for NR1I2
Band16|16 B3Start38,068,685bp[2]
End38,115,186bp[2]
RNA expression pattern
Bgee
HumanMouse (ortholog)
Top expressed in
  • right lobe of liver

  • jejunal mucosa

  • mucosa of transverse colon

  • duodenum

  • rectum

  • mucosa of ileum

  • mucosa of sigmoid colon

  • gallbladder

  • cecum

  • appendix
Top expressed in
  • duodenum

  • jejunum

  • crypt of lieberkuhn of small intestine

  • colon

  • left colon

  • left lobe of liver

  • ileum

  • female urethra

  • lumbar subsegment of spinal cord

  • intestinal villus
More reference expression data
BioGPS


More reference expression data
Gene ontology
Molecular function
Cellular component
Biological process
Sources:Amigo /QuickGO
Orthologs
SpeciesHumanMouse
Entrez

8856

18171

Ensembl

ENSG00000144852

ENSMUSG00000022809

UniProt

O75469

O54915

RefSeq (mRNA)

NM_033013
NM_003889
NM_022002

NM_001098404
NM_010936

RefSeq (protein)

NP_003880
NP_071285
NP_148934

NP_001091874
NP_035066

Location (UCSC)Chr 3: 119.78 – 119.82 MbChr 16: 38.07 – 38.12 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

In the field ofmolecular biology, thepregnane X receptor (PXR), also known as the steroid and xenobiotic sensing nuclear receptor (SXR) or nuclear receptor subfamily 1, group I, member 2 (NR1I2) is aprotein that in humans is encoded by theNR1I2 (nuclear Receptor subfamily 1, group I, member 2) gene.[5][6][7]

Function

[edit]

PXR is anuclear receptor whose primary function is to sense the presence of foreign toxic substances and in responseup regulate the expression of proteins involved in thedetoxification and clearance of these substances from the body.[8] PXR belongs to the nuclear receptor superfamily, members of which aretranscription factors characterized by a ligand-binding domain and aDNA-binding domain. PXR is a transcriptional regulator of thecytochrome P450 geneCYP3A4, binding to the response element of the CYP3A4 promoter as a heterodimer with the 9-cis retinoic acid receptorRXR. It is activated by a range of compounds that induce CYP3A4, includingdexamethasone andrifampicin.[7][9]

Ligands

[edit]

Agonists

[edit]

PXR is activated by a large number ofendogenous andexogenous chemicals[8] includingsteroids (e.g.,progesterone,17α-hydroxyprogesterone,17α-hydroxypregnenolone,5α-dihydroprogesterone,5β-dihydroprogesterone,allopregnanolone,corticosterone,cyproterone acetate,spironolactone,dexamethasone,mifepristone),antibiotics (e.g.,rifampicin,rifaximin),antimycotics,bile acids,hyperforin (a constituent ofSt. John's Wort), and other compounds such asmeclizine,paclitaxel,cafestol,[10] andforskolin.[11][12]

Antagonists

[edit]

Ketoconazole is an example of one of the relatively few-knownantagonists of the PXR.[13][14] SPA70 (also known as LC-1) was recently identified and characterized as a potent and selective PXR antagonist.[15][16]

Mechanism

[edit]

Like othertype II nuclear receptors, when activated, it forms a heterodimer with theretinoid X receptor, and binds tohormone response elements on DNA which elicits expression ofgene products.[8]

One of the primary targets of PXR activation is the induction ofCYP3A4, an importantphase I oxidativeenzyme that is responsible for themetabolism of manydrugs.[6][7] In addition, PXR up regulates the expression of phase II conjugating enzymes such asglutathione S-transferase[17] and phase III transport uptake andefflux proteins such asOATP2[18] andMDR1.[19][20]

See also

[edit]

References

[edit]
  1. ^abcGRCh38: Ensembl release 89: ENSG00000144852 –Ensembl, May 2017
  2. ^abcGRCm38: Ensembl release 89: ENSMUSG00000022809 –Ensembl, May 2017
  3. ^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^Entrez result for NR1I2.
  6. ^abLehmann JM, McKee DD, Watson MA, Willson TM, Moore JT, Kliewer SA (September 1998)."The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions".The Journal of Clinical Investigation.102 (5):1016–23.doi:10.1172/JCI3703.PMC 508967.PMID 9727070.
  7. ^abcBertilsson G, Heidrich J, Svensson K, Asman M, Jendeberg L, Sydow-Bäckman M, Ohlsson R, Postlind H, Blomquist P, Berkenstam A (October 1998)."Identification of a human nuclear receptor defines a new signaling pathway for CYP3A induction".Proceedings of the National Academy of Sciences of the United States of America.95 (21):12208–13.Bibcode:1998PNAS...9512208B.doi:10.1073/pnas.95.21.12208.PMC 22810.PMID 9770465.
  8. ^abcKliewer SA, Goodwin B, Willson TM (October 2002)."The nuclear pregnane X receptor: a key regulator of xenobiotic metabolism".Endocrine Reviews.23 (5):687–702.doi:10.1210/er.2001-0038.PMID 12372848.
  9. ^"Entrez Gene: NR1I2 nuclear receptor subfamily 1, group I, member 2".
  10. ^Ricketts ML, Boekschoten MV, Kreeft AJ, Hooiveld GJ, Moen CJ, Müller M, Frants RR, Kasanmoentalib S, Post SM, Princen HM, Porter JG, Katan MB, Hofker MH, Moore DD (July 2007)."The cholesterol-raising factor from coffee beans, cafestol, as an agonist ligand for the farnesoid and pregnane X receptors".Molecular Endocrinology.21 (7):1603–16.doi:10.1210/me.2007-0133.PMID 17456796.
  11. ^Kaur J, Sodhi RK, Madan J, Chahal SK, Kumar R (February 2018). "Forskolin convalesces memory in high fat diet-induced dementia in wistar rats-Plausible role of pregnane x receptors".Pharmacological Reports.70 (1):161–171.doi:10.1016/j.pharep.2017.07.009.PMID 29367103.S2CID 3872389.
  12. ^Ding X, Staudinger JL (February 2005). "Induction of drug metabolism by forskolin: the role of the pregnane X receptor and the protein kinase a signal transduction pathway".The Journal of Pharmacology and Experimental Therapeutics.312 (2):849–856.doi:10.1124/jpet.104.076331.PMID 15459237.S2CID 8056821.
  13. ^Li H, Dou W, Padikkala E, Mani S (November 2013)."Reverse yeast two-hybrid system to identify mammalian nuclear receptor residues that interact with ligands and/or antagonists".Journal of Visualized Experiments (81) e51085.doi:10.3791/51085.PMC 3904218.PMID 24300333.
  14. ^Mani S, Dou W, Redinbo MR (February 2013)."PXR antagonists and implication in drug metabolism".Drug Metabolism Reviews.45 (1):60–72.doi:10.3109/03602532.2012.746363.PMC 3583015.PMID 23330542.
  15. ^Lin W, Goktug AN, Wu J, Currier DG, Chen T (December 2017)."High-Throughput Screening Identifies 1,4,5-Substituted 1,2,3-Triazole Analogs as Potent and Specific Antagonists of Pregnane X Receptor".Assay and Drug Development Technologies.15 (8):383–394.doi:10.1089/adt.2017.809.PMC 5731549.PMID 29112465.
  16. ^Lin W, Wang YM, Chai SC, Lv L, Zheng J, Wu J, Zhang Q, Wang YD, Griffin PR, Chen T (September 2017)."SPA70 is a potent antagonist of human pregnane X receptor".Nature Communications.8 (1): 741.Bibcode:2017NatCo...8..741L.doi:10.1038/s41467-017-00780-5.PMC 5622171.PMID 28963450.
  17. ^Falkner KC, Pinaire JA, Xiao GH, Geoghegan TE, Prough RA (September 2001)."Regulation of the rat glutathione S-transferase A2 gene by glucocorticoids: involvement of both the glucocorticoid and pregnane X receptors".Molecular Pharmacology.60 (3):611–9.PMID 11502894.
  18. ^Staudinger JL, Goodwin B, Jones SA, Hawkins-Brown D, MacKenzie KI, LaTour A, Liu Y, Klaassen CD, Brown KK, Reinhard J, Willson TM, Koller BH, Kliewer SA (March 2001)."The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity".Proceedings of the National Academy of Sciences of the United States of America.98 (6):3369–74.Bibcode:2001PNAS...98.3369S.doi:10.1073/pnas.051551698.PMC 30660.PMID 11248085.
  19. ^Synold TW, Dussault I, Forman BM (May 2001). "The orphan nuclear receptor SXR coordinately regulates drug metabolism and efflux".Nature Medicine.7 (5):584–90.doi:10.1038/87912.PMID 11329060.S2CID 34155288.
  20. ^Geick A, Eichelbaum M, Burk O (May 2001)."Nuclear receptor response elements mediate induction of intestinal MDR1 by rifampin".The Journal of Biological Chemistry.276 (18):14581–7.doi:10.1074/jbc.M010173200.PMID 11297522.

Further reading

[edit]

External links

[edit]

This article incorporates text from theUnited States National Library of Medicine, which is in thepublic domain.

PDB gallery
  • 1ilg: Crystal Structure of Apo Human Pregnane X Receptor Ligand Binding Domain
    1ilg: Crystal Structure of Apo Human Pregnane X Receptor Ligand Binding Domain
  • 1ilh: Crystal Structure of Human Pregnane X Receptor Ligand Binding Domain Bound to SR12813
    1ilh: Crystal Structure of Human Pregnane X Receptor Ligand Binding Domain Bound to SR12813
  • 1m13: Crystal Structure of the Human Pregane X Receptor Ligand Binding Domain in Complex with Hyperforin, a Constituent of St. John's Wort
    1m13: Crystal Structure of the Human Pregane X Receptor Ligand Binding Domain in Complex with Hyperforin, a Constituent of St. John's Wort
  • 1nrl: Crystal Structure of the human PXR-LBD in complex with an SRC-1 coactivator peptide and SR12813
    1nrl: Crystal Structure of the human PXR-LBD in complex with an SRC-1 coactivator peptide and SR12813
  • 1skx: Structural Disorder in the Complex of Human PXR and the Macrolide Antibiotic Rifampicin
    1skx: Structural Disorder in the Complex of Human PXR and the Macrolide Antibiotic Rifampicin
  • 2o9i: Crystal Structure of the Human Pregnane X Receptor LBD in complex with an SRC-1 coactivator peptide and T0901317
    2o9i: Crystal Structure of the Human Pregnane X Receptor LBD in complex with an SRC-1 coactivator peptide and T0901317
(1) Basic domains
(1.1) Basicleucine zipper (bZIP)
(1.2) Basic helix-loop-helix (bHLH)
Group A
Group B
Group C
bHLH-PAS
Group D
Group E
Group F
bHLH-COE
(1.3)bHLH-ZIP
(1.4) NF-1
(1.5) RF-X
(1.6) Basic helix-span-helix (bHSH)
(2)Zinc finger DNA-binding domains
(2.1)Nuclear receptor(Cys4)
subfamily 1
subfamily 2
subfamily 3
subfamily 4
subfamily 5
subfamily 6
subfamily 0
(2.2) Other Cys4
(2.3) Cys2His2
(2.4) Cys6
(2.5) Alternating composition
(2.6) WRKY
(3.1)Homeodomain
Antennapedia
ANTP class
protoHOX
Hox-like
metaHOX
NK-like
other
(3.2) Paired box
(3.3)Fork head /winged helix
(3.4)Heat shock factors
(3.5) Tryptophan clusters
(3.6) TEA domain
  • transcriptional enhancer factor
(4)β-Scaffold factors with minor groove contacts
(4.1)Rel homology region
(4.2)STAT
(4.3) p53-like
(4.4)MADS box
(4.6)TATA-binding proteins
(4.7)High-mobility group
(4.9) Grainyhead
(4.10) Cold-shock domain
(4.11) Runt
(0) Other transcription factors
(0.2) HMGI(Y)
(0.3)Pocket domain
(0.5)AP-2/EREBP-related factors
(0.6) Miscellaneous
CARTooltip Constitutive androstane receptor
PXRTooltip Pregnane X receptor
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