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PDBsum entry 1ilh

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Gene regulation PDB id
1ilh
Jmol
Contents
Protein chain
270 a.a. *
Ligands
SRL
Waters ×166
* Residue conservation analysis
PDB id:
1ilh
Name: Gene regulation
Title: Crystal structure of human pregnane x receptor ligand binding domain bound to sr12813
Structure: Orphan nuclear receptor pxr. Chain: a. Fragment: ligand binding domain. Synonym: pregnane x receptor. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: pxr. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
Biol. unit: Dimer (from PQS)
Resolution:
2.76Å     R-factor:   0.222     R-free:   0.282
Authors: R.E.Watkins,M.R.Redinbo
Key ref:
R.E.Watkins et al. (2001). The human nuclear xenobiotic receptor PXR: structural determinants of directed promiscuity. Science, 292, 2329-2333. PubMed id: 11408620 DOI: 10.1126/science.1060762
Date:
08-May-01     Release date:   27-Jun-01    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
O75469  (NR1I2_HUMAN) -  Nuclear receptor subfamily 1 group I member 2
Seq:
Struc:
434 a.a.
270 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     nucleus   1 term 
  Biological process     steroid hormone mediated signaling pathway   2 terms 
  Biochemical function     DNA binding     5 terms  

 

 
DOI no: 10.1126/science.1060762 Science 292:2329-2333 (2001)
PubMed id: 11408620  
 
 
The human nuclear xenobiotic receptor PXR: structural determinants of directed promiscuity.
R.E.Watkins, G.B.Wisely, L.B.Moore, J.L.Collins, M.H.Lambert, S.P.Williams, T.M.Willson, S.A.Kliewer, M.R.Redinbo.
 
  ABSTRACT  
 
The human nuclear pregnane X receptor (hPXR) activates cytochrome P450-3A expression in response to a wide variety of xenobiotics and plays a critical role in mediating dangerous drug-drug interactions. We present the crystal structures of the ligand-binding domain of hPXR both alone and in complex with the cholesterol-lowering drug SR12813 at resolutions of 2.5 and 2.75 angstroms, respectively. The hydrophobic ligand-binding cavity of hPXR contains a small number of polar residues, permitting SR12813 to bind in three distinct orientations. The position and nature of these polar residues were found to be critical for establishing the precise pharmacologic activation profile of PXR. Our findings provide important insights into how hPXR detects xenobiotics and may prove useful in predicting and avoiding drug-drug interactions.
 
  Selected figure(s)  
 
Figure 1.
Fig. 1. (A) Structure of the LBD of the human xenobiotic receptor PXR. Residues 142 to 177 and 198 to 431 of hPXR in complex with three orientations of SR12813 are shown; helices are in red and strands are in green, including the two novel strands, 1 and 1' that complete the five-stranded antiparallel sheet observed in this structure. Secondary structural elements are numbered according to the RXR structure (19). See also Web fig. 1 (25). (B) hPXR-LDB electron density: unbiased (F[obs] F[calc]) electron density into which the novel 1/ 1' strands (residues 210 to 228) of hPXR were traced (2.75 Å resolution, contoured at 1.2 ). (C and D) The ligand-binding cavity of hPXR. A cutaway view of the binding cavity, including electrostatic surface potentials (positive in blue, negative in red), reveals a relatively smooth, uncharged surface. The cavity is enclosed by portions of five helices ( 3, 5, 7, 10, and AF), three strands ( 1, 3, and 4), and three loops (the 10- AF region and the two mobile regions between 4 and 7 and from residue 198 to 1). Select residues lining the cavity are indicated. In particular, the positions of the following polar residues that contact SR12813 are indicated in red: Ser208, Ser247, Gln285, His407, and Arg410. Regions of the surface 309-321 loop, which may facilitate the expansion of the ligand-binding pocket, are also shown, including the conserved hydrophobic residues Phe^315, Leu318, Leu319, and Leu320.
Figure 2.
Fig. 2. Three experimentally observed positions of SR12813 in the ligand-binding pocket of hPXR. Intermolecular interactions are shown with amino acid side chains in blue and the C atom as a sphere. The positions 1, 2, and 3 of SR12813 are rendered in cyan, purple, and orange, respectively. Equivalent side chains from the apo structure are shown in white. A small number of residues undergo rotamer shifts (Met243, Cys284, and His407) or small shifts in position (Ser208 and Leu209) upon SR12813 binding. Residues mutated to examine the specificity of mouse PXR are underlined. (A) Position 1 makes van der Waals contacts with eight side chains, and forms one 3.0 Å hydrogen bond with Ser247. (B) Position 2 makes van der Waals contacts with seven side chains, and forms one 2.8 Å hydrogen bond with His407. (C) Position 3 makes van der Waals contacts with six side chains, and forms three hydrogen bonds with Ser247, Gln285, and Ser208, which forms a water-mediated hydrogen bond. See also Web table 2 and Web fig. 2 (25).
 
  The above figures are reprinted by permission from the AAAs: Science (2001, 292, 2329-2333) copyright 2001.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21311750 I.Bailey, G.G.Gibson, K.Plant, M.Graham, and N.Plant (2011).
A PXR-mediated negative feedback loop attenuates the expression of CYP3A in response to the PXR agonist pregnenalone-16α-carbonitrile.
  PLoS One, 6, e16703.  
21091656 J.Cheng, X.Ma, and F.J.Gonzalez (2011).
Pregnane X receptor- and CYP3A4-humanized mouse models and their applications.
  Br J Pharmacol, 163, 461-468.  
20692346 J.J.Kerrigan, Q.Xie, R.S.Ames, and Q.Lu (2011).
Production of protein complexes via co-expression.
  Protein Expr Purif, 75, 1.  
20942813 J.Yang, X.Luan, H.Gui, P.Yan, D.Yang, X.Song, W.Liu, G.Hu, and B.Yan (2011).
Byakangelicin induces cytochrome P450 3A4 expression via transactivation of pregnane X receptors in human hepatocytes.
  Br J Pharmacol, 162, 441-451.  
21264225 K.M.Peters, B.E.Brooks, M.A.Schumacher, R.A.Skurray, R.G.Brennan, and M.H.Brown (2011).
A Single Acidic Residue Can Guide Binding Site Selection but Does Not Govern QacR Cationic-Drug Affinity.
  PLoS One, 6, e15974.
PDB code: 3pm1
21376070 L.C.Mota, C.Barfield, J.P.Hernandez, and W.S.Baldwin (2011).
Nonylphenol-mediated CYP induction is PXR-dependent: The use of humanized mice and human hepatocytes suggests that hPXR is less sensitive than mouse PXR to nonylphenol treatment.
  Toxicol Appl Pharmacol, 252, 259-267.  
21291553 M.D.Krasowski, N.Ai, L.R.Hagey, E.M.Kollitz, S.W.Kullman, E.J.Reschly, and S.Ekins (2011).
The evolution of farnesoid X, vitamin D, and pregnane X receptors: insights from the green-spotted pufferfish (Tetraodon nigriviridis) and other non-mammalian species.
  BMC Biochem, 12, 5.  
  21117944 Y.H.Liu, S.L.Mo, H.C.Bi, B.F.Hu, C.G.Li, Y.T.Wang, L.Huang, M.Huang, W.Duan, J.P.Liu, M.Q.Wei, and S.F.Zhou (2011).
Regulation of human pregnane X receptor and its target gene cytochrome P450 3A4 by Chinese herbal compounds and a molecular docking study.
  Xenobiotica, 41, 259-280.  
19638645 A.F.Hofmann, L.R.Hagey, and M.D.Krasowski (2010).
Bile salts of vertebrates: structural variation and possible evolutionary significance.
  J Lipid Res, 51, 226-246.  
20727377 A.H.Tolson, and H.Wang (2010).
Regulation of drug-metabolizing enzymes by xenobiotic receptors: PXR and CAR.
  Adv Drug Deliv Rev, 62, 1238-1249.  
20063036 A.le Maire, W.Bourguet, and P.Balaguer (2010).
A structural view of nuclear hormone receptor: endocrine disruptor interactions.
  Cell Mol Life Sci, 67, 1219-1237.
PDB code: 3kwy
20113149 H.Li, and H.Wang (2010).
Activation of xenobiotic receptors: driving into the nucleus.
  Expert Opin Drug Metab Toxicol, 6, 409-426.  
20580544 H.Wade (2010).
MD recognition by MDR gene regulators.
  Curr Opin Struct Biol, 20, 489-496.  
20723571 L.Jin, and Y.Li (2010).
Structural and functional insights into nuclear receptor signaling.
  Adv Drug Deliv Rev, 62, 1218-1226.  
20151218 N.S.Luke, M.J.DeVito, I.Shah, and H.A.El-Masri (2010).
Development of a quantitative model of pregnane X receptor (PXR) mediated xenobiotic metabolizing enzyme induction.
  Bull Math Biol, 72, 1799-1819.  
20377437 P.Wasserman, and D.S.Rubin (2010).
Highly prevalent vitamin D deficiency and insufficiency in an urban cohort of HIV-infected men under care.
  AIDS Patient Care STDS, 24, 223-227.  
20372994 S.Mukherjee, and S.Mani (2010).
Orphan nuclear receptors as targets for drug development.
  Pharm Res, 27, 1439-1468.  
20691230 T.Chen (2010).
Overcoming drug resistance by regulating nuclear receptors.
  Adv Drug Deliv Rev, 62, 1257-1264.  
19924124 V.Hafner, M.Jäger, A.K.Matthée, R.Ding, J.Burhenne, W.E.Haefeli, and G.Mikus (2010).
Effect of simultaneous induction and inhibition of CYP3A by St John's Wort and ritonavir on CYP3A activity.
  Clin Pharmacol Ther, 87, 191-196.  
20861838 X.He, P.Szewczyk, A.Karyakin, M.Evin, W.X.Hong, Q.Zhang, and G.Chang (2010).
Structure of a cation-bound multidrug and toxic compound extrusion transporter.
  Nature, 467, 991-994.
PDB codes: 3mkt 3mku
19415465 A.Biswas, S.Mani, M.R.Redinbo, M.D.Krasowski, H.Li, and S.Ekins (2009).
Elucidating the 'Jekyll and Hyde' nature of PXR: the case for discovering antagonists or allosteric antagonists.
  Pharm Res, 26, 1807-1815.  
19427329 A.di Masi, E.De Marinis, P.Ascenzi, and M.Marino (2009).
Nuclear receptors CAR and PXR: Molecular, functional, and biomedical aspects.
  Mol Aspects Med, 30, 297-343.  
19856963 C.H.Ngan, D.Beglov, A.N.Rudnitskaya, D.Kozakov, D.J.Waxman, and S.Vajda (2009).
The structural basis of pregnane X receptor binding promiscuity.
  Biochemistry, 48, 11572-11581.  
18978041 C.W.Li, G.K.Dinh, and J.D.Chen (2009).
Preferential physical and functional interaction of pregnane X receptor with the SMRTalpha isoform.
  Mol Pharmacol, 75, 363-373.  
  19240808 C.Zhou, S.Verma, and B.Blumberg (2009).
The steroid and xenobiotic receptor (SXR), beyond xenobiotic metabolism.
  Nucl Recept Signal, 7, e001.  
19231985 H.Nikaido (2009).
Multidrug resistance in bacteria.
  Annu Rev Biochem, 78, 119-146.  
20871735 J.P.Hernandez, L.C.Mota, and W.S.Baldwin (2009).
Activation of CAR and PXR by Dietary, Environmental and Occupational Chemicals Alters Drug Metabolism, Intermediary Metabolism, and Cell Proliferation.
  Curr Pharmacogenomics Person Med, 7, 81.  
19429508 N.Ai, M.D.Krasowski, W.J.Welsh, and S.Ekins (2009).
Understanding nuclear receptors using computational methods.
  Drug Discov Today, 14, 486-494.  
19129222 N.Hariparsad, X.Chu, J.Yabut, P.Labhart, D.P.Hartley, X.Dai, and R.Evers (2009).
Identification of pregnane-X receptor target genes and coactivator and corepressor binding to promoter elements in human hepatocytes.
  Nucleic Acids Res, 37, 1160-1173.  
19626711 S.Burendahl, C.Danciulescu, and L.Nilsson (2009).
Ligand unbinding from the estrogen receptor: a computational study of pathways and ligand specificity.
  Proteins, 77, 842-856.  
20011107 S.Ekins, S.Kortagere, M.Iyer, E.J.Reschly, M.A.Lill, M.R.Redinbo, and M.D.Krasowski (2009).
Challenges predicting ligand-receptor interactions of promiscuous proteins: the nuclear receptor PXR.
  PLoS Comput Biol, 5, e1000594.  
19325113 S.G.Aller, J.Yu, A.Ward, Y.Weng, S.Chittaboina, R.Zhuo, P.M.Harrell, Y.T.Trinh, Q.Zhang, I.L.Urbatsch, and G.Chang (2009).
Structure of P-glycoprotein reveals a molecular basis for poly-specific drug binding.
  Science, 323, 1718-1722.
PDB codes: 3g5u 3g60 3g61
19115096 S.Kortagere, D.Chekmarev, W.J.Welsh, and S.Ekins (2009).
Hybrid scoring and classification approaches to predict human pregnane x receptor activators.
  Pharm Res, 26, 1001-1011.  
18832183 W.S.Baldwin, and J.A.Roling (2009).
A concentration addition model for the activation of the constitutive androstane receptor by xenobiotic mixtures.
  Toxicol Sci, 107, 93.  
19251824 Y.S.Lin, K.Yasuda, M.Assem, C.Cline, J.Barber, C.W.Li, V.Kholodovych, N.Ai, J.D.Chen, W.J.Welsh, S.Ekins, and E.G.Schuetz (2009).
The major human pregnane X receptor (PXR) splice variant, PXR.2, exhibits significantly diminished ligand-activated transcriptional regulation.
  Drug Metab Dispos, 37, 1295-1304.  
19144646 Y.Xie, S.Ke, N.Ouyang, J.He, W.Xie, M.T.Bedford, and Y.Tian (2009).
Epigenetic regulation of transcriptional activity of pregnane X receptor by protein arginine methyltransferase 1.
  J Biol Chem, 284, 9199-9205.  
19158313 Z.Duniec-Dmuchowski, H.L.Fang, S.C.Strom, E.Ellis, M.Runge-Morris, and T.A.Kocarek (2009).
Human pregnane X receptor activation and CYP3A4/CYP2B6 induction by 2,3-oxidosqualene:lanosterol cyclase inhibition.
  Drug Metab Dispos, 37, 900-908.  
18547065 A.Khandelwal, M.D.Krasowski, E.J.Reschly, M.W.Sinz, P.W.Swaan, and S.Ekins (2008).
Machine learning methods and docking for predicting human pregnane X receptor activation.
  Chem Res Toxicol, 21, 1457-1467.  
19018724 B.Zhang, W.Xie, and M.D.Krasowski (2008).
PXR: a xenobiotic receptor of diverse function implicated in pharmacogenetics.
  Pharmacogenomics, 9, 1695-1709.  
18768384 D.G.Teotico, J.J.Bischof, L.Peng, S.A.Kliewer, and M.R.Redinbo (2008).
Structural basis of human pregnane X receptor activation by the hops constituent colupulone.
  Mol Pharmacol, 74, 1512-1520.  
18617990 D.G.Teotico, M.L.Frazier, F.Ding, N.V.Dokholyan, B.R.Temple, and M.R.Redinbo (2008).
Active nuclear receptors exhibit highly correlated AF-2 domain motions.
  PLoS Comput Biol, 4, e1000111.  
18362391 E.J.Reschly, N.Ai, S.Ekins, W.J.Welsh, L.R.Hagey, A.F.Hofmann, and M.D.Krasowski (2008).
Evolution of the bile salt nuclear receptor FXR in vertebrates.
  J Lipid Res, 49, 1577-1587.  
18781911 H.Wang, and L.M.Tompkins (2008).
CYP2B6: new insights into a historically overlooked cytochrome P450 isozyme.
  Curr Drug Metab, 9, 598-610.  
18332862 I.S.Haslam, K.Jones, T.Coleman, and N.L.Simmons (2008).
Rifampin and digoxin induction of MDR1 expression and function in human intestinal (T84) epithelial cells.
  Br J Pharmacol, 154, 246-255.  
18370862 J.J.Cali, A.Niles, M.P.Valley, M.A.O'Brien, T.L.Riss, and J.Shultz (2008).
Bioluminescent assays for ADMET.
  Expert Opin Drug Metab Toxicol, 4, 103-120.  
  18629309 M.R.Milnes, A.Garcia, E.Grossman, F.Grün, J.Shiotsugu, M.M.Tabb, Y.Kawashima, Y.Katsu, H.Watanabe, T.Iguchi, and B.Blumberg (2008).
Activation of steroid and xenobiotic receptor (SXR, NR1I2) and its orthologs in laboratory, toxicologic, and genome model species.
  Environ Health Perspect, 116, 880-885.  
18686044 M.Sinz, G.Wallace, and J.Sahi (2008).
Current industrial practices in assessing CYP450 enzyme induction: preclinical and clinical.
  AAPS J, 10, 391-400.  
19011999 N.Rokutanda, T.Iwasaki, H.Odawara, R.Nagaoka, W.Miyazaki, A.Takeshita, Y.Koibuchi, J.Horiguchi, N.Shimokawa, Y.Iino, Y.Morishita, and N.Koibuchi (2008).
Augmentation of estrogen receptor-mediated transcription by steroid and xenobiotic receptor.
  Endocrine, 33, 305-316.  
18618097 O.Pelkonen, M.Turpeinen, J.Hakkola, P.Honkakoski, J.Hukkanen, and H.Raunio (2008).
Inhibition and induction of human cytochrome P450 enzymes: current status.
  Arch Toxicol, 82, 667-715.  
18384689 S.Ekins, E.J.Reschly, L.R.Hagey, and M.D.Krasowski (2008).
Evolution of pharmacologic specificity in the pregnane X receptor.
  BMC Evol Biol, 8, 103.  
17629950 S.H.Mellon, W.Gong, and M.D.Schonemann (2008).
Endogenous and synthetic neurosteroids in treatment of Niemann-Pick Type C disease.
  Brain Res Rev, 57, 410-420.  
18456871 W.Wang, W.W.Prosise, J.Chen, S.S.Taremi, H.V.Le, V.Madison, X.Cui, A.Thomas, K.C.Cheng, and C.A.Lesburg (2008).
Construction and characterization of a fully active PXR/SRC-1 tethered protein with increased stability.
  Protein Eng Des Sel, 21, 425-433.
PDB codes: 3ctb 3ctc 3hvl
17828778 A.Martínez, A.Márquez, J.Mendoza, C.Taxonera, M.Fernández-Arquero, M.Díaz-Rubio, E.G.de la Concha, and E.Urcelay (2007).
Role of the PXR gene locus in inflammatory bowel diseases.
  Inflamm Bowel Dis, 13, 1484-1487.  
17436120 C.B.Pollock, M.B.Rogatcheva, and L.B.Schook (2007).
Comparative genomics of xenobiotic metabolism: a porcine-human PXR gene comparison.
  Mamm Genome, 18, 210-219.  
17429392 C.F.Higgins (2007).
Multiple molecular mechanisms for multidrug resistance transporters.
  Nature, 446, 749-757.  
17210444 D.Kluth, A.Banning, I.Paur, R.Blomhoff, and R.Brigelius-Flohé (2007).
Modulation of pregnane X receptor- and electrophile responsive element-mediated gene expression by dietary polyphenolic compounds.
  Free Radic Biol Med, 42, 315-325.  
17223708 E.Wright, J.Vincent, and E.J.Fernandez (2007).
Thermodynamic characterization of the interaction between CAR-RXR and SRC-1 peptide by isothermal titration calorimetry.
  Biochemistry, 46, 862-870.  
17483497 J.P.Hernandez, W.Huang, L.M.Chapman, S.Chua, D.D.Moore, and W.S.Baldwin (2007).
The environmental estrogen, nonylphenol, activates the constitutive androstane receptor.
  Toxicol Sci, 98, 416-426.  
17468738 K.W.Nettles, J.B.Bruning, G.Gil, E.E.O'Neill, J.Nowak, Y.Guo, A.Hughs, Y.Kim, E.R.DeSombre, R.Dilis, R.N.Hanson, A.Joachimiak, and G.L.Greene (2007).
Structural plasticity in the oestrogen receptor ligand-binding domain.
  EMBO Rep, 8, 563-568.
PDB code: 2p15
17936931 L.M.Tompkins, and A.D.Wallace (2007).
Mechanisms of cytochrome P450 induction.
  J Biochem Mol Toxicol, 21, 176-181.  
17875939 M.Igarashi, Y.Yogiashi, M.Mihara, I.Takada, H.Kitagawa, and S.Kato (2007).
Vitamin K induces osteoblast differentiation through pregnane X receptor-mediated transcriptional control of the Msx2 gene.
  Mol Cell Biol, 27, 7947-7954.  
17159924 O.Lomovskaya, H.I.Zgurskaya, M.Totrov, and W.J.Watkins (2007).
Waltzing transporters and 'the dance macabre' between humans and bacteria.
  Nat Rev Drug Discov, 6, 56-65.  
17576789 S.Ekins, C.Chang, S.Mani, M.D.Krasowski, E.J.Reschly, M.Iyer, V.Kholodovych, N.Ai, W.J.Welsh, M.Sinz, P.W.Swaan, R.Patel, and K.Bachmann (2007).
Human pregnane X receptor antagonists and agonists define molecular requirements for different binding sites.
  Mol Pharmacol, 72, 592-603.  
17651807 S.H.Mellon (2007).
Neurosteroid regulation of central nervous system development.
  Pharmacol Ther, 116, 107-124.  
17284330 Y.E.Timsit, and M.Negishi (2007).
CAR and PXR: the xenobiotic-sensing receptors.
  Steroids, 72, 231-246.  
17429319 Y.P.Lim, and J.D.Huang (2007).
Pregnane X receptor polymorphism affects CYP3A4 induction via a ligand-dependent interaction with steroid receptor coactivator-1.
  Pharmacogenet Genomics, 17, 369-382.  
17215127 Y.Xue, E.Chao, W.J.Zuercher, T.M.Willson, J.L.Collins, and M.R.Redinbo (2007).
Crystal structure of the PXR-T1317 complex provides a scaffold to examine the potential for receptor antagonism.
  Bioorg Med Chem, 15, 2156-2166.
PDB code: 2o9i
16724925 E.J.Reschly, and M.D.Krasowski (2006).
Evolution and function of the NR1I nuclear hormone receptor subfamily (VDR, PXR, and CAR) with respect to metabolism of xenobiotics and endogenous compounds.
  Curr Drug Metab, 7, 349-365.  
16480505 J.Chen, and K.Raymond (2006).
Roles of rifampicin in drug-drug interactions: underlying molecular mechanisms involving the nuclear pregnane X receptor.
  Ann Clin Microbiol Antimicrob, 5, 3.  
16718615 J.H.Lin (2006).
CYP induction-mediated drug interactions: in vitro assessment and clinical implications.
  Pharm Res, 23, 1089-1116.  
17125405 J.L.Staudinger, X.Ding, and K.Lichti (2006).
Pregnane X receptor and natural products: beyond drug-drug interactions.
  Expert Opin Drug Metab Toxicol, 2, 847-857.  
16475182 J.Seetharaman, D.Kumaran, J.B.Bonanno, S.K.Burley, and S.Swaminathan (2006).
Crystal structure of a putative HTH-type transcriptional regulator yxaF from Bacillus subtilis.
  Proteins, 63, 1087-1091.
PDB code: 1sgm
16863441 M.Iyer, E.J.Reschly, and M.D.Krasowski (2006).
Functional evolution of the pregnane X receptor.
  Expert Opin Drug Metab Toxicol, 2, 381-397.  
16805946 M.Murray (2006).
Role of CYP pharmacogenetics and drug-drug interactions in the efficacy and safety of atypical and other antipsychotic agents.
  J Pharm Pharmacol, 58, 871-885.  
17526937 R.Nagaoka, T.Iwasaki, N.Rokutanda, A.Takeshita, Y.Koibuchi, J.Horiguchi, N.Shimokawa, Y.Iino, Y.Morishita, and N.Koibuchi (2006).
Tamoxifen activates CYP3A4 and MDR1 genes through steroid and xenobiotic receptor in breast cancer cells.
  Endocrine, 30, 261-268.  
16940355 S.J.Langmade, S.E.Gale, A.Frolov, I.Mohri, K.Suzuki, S.H.Mellon, S.U.Walkley, D.F.Covey, J.E.Schaffer, and D.S.Ory (2006).
Pregnane X receptor (PXR) activation: a mechanism for neuroprotection in a mouse model of Niemann-Pick C disease.
  Proc Natl Acad Sci U S A, 103, 13807-13812.  
16834332 S.M.Noble, V.E.Carnahan, L.B.Moore, T.Luntz, H.Wang, O.R.Ittoop, J.B.Stimmel, P.R.Davis-Searles, R.E.Watkins, G.B.Wisely, E.LeCluyse, A.Tripathy, D.P.McDonnell, and M.R.Redinbo (2006).
Human PXR forms a tryptophan zipper-mediated homodimer.
  Biochemistry, 45, 8579-8589.  
16862575 S.S.Rajan, X.Yang, L.Shuvalova, F.Collart, and W.F.Anderson (2006).
Crystal structure of YfiR, an unusual TetR/CamR-type putative transcriptional regulator from Bacillus subtilis.
  Proteins, 65, 255-257.
PDB code: 1rkt
15616833 B.Windshügel, J.Jyrkkärinne, A.Poso, P.Honkakoski, and W.Sippl (2005).
Molecular dynamics simulations of the human CAR ligand-binding domain: deciphering the molecular basis for constitutive activity.
  J Mol Model, 11, 69-79.  
16166543 E.W.Yu, J.R.Aires, G.McDermott, and H.Nikaido (2005).
A periplasmic drug-binding site of the AcrB multidrug efflux pump: a crystallographic and site-directed mutagenesis study.
  J Bacteriol, 187, 6804-6815.
PDB codes: 1t9t 1t9u 1t9v 1t9w 1t9x 1t9y
  16508121 J.Vincent, L.Shan, M.Fan, J.S.Brunzelle, B.M.Forman, and E.J.Fernandez (2005).
Crystallographic analysis of murine constitutive androstane receptor ligand-binding domain complexed with 5alpha-androst-16-en-3alpha-ol.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 61, 156-159.  
16197547 M.D.Krasowski, K.Yasuda, L.R.Hagey, and E.G.Schuetz (2005).
Evolutionary selection across the nuclear hormone receptor superfamily with a focus on the NR1I subfamily (vitamin D, pregnane X, and constitutive androstane receptors).
  Nucl Recept, 3, 2.  
15718292 M.D.Krasowski, K.Yasuda, L.R.Hagey, and E.G.Schuetz (2005).
Evolution of the pregnane x receptor: adaptation to cross-species differences in biliary bile salts.
  Mol Endocrinol, 19, 1720-1739.  
15642254 M.Newcomer (2005).
A response to reimportation.
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15578590 P.W.Jurutka, P.D.Thompson, G.K.Whitfield, K.R.Eichhorst, N.Hall, C.E.Dominguez, J.C.Hsieh, C.A.Haussler, and M.R.Haussler (2005).
Molecular and functional comparison of 1,25-dihydroxyvitamin D(3) and the novel vitamin D receptor ligand, lithocholic acid, in activating transcription of cytochrome P450 3A4.
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16270281 R.Brigelius-Flohé, D.Kluth, and A.Banning (2005).
Is there a future for antioxidants in atherogenesis?
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15858847 R.G.Tirona, and R.B.Kim (2005).
Nuclear receptors and drug disposition gene regulation.
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15710871 S.A.Kliewer (2005).
Cholesterol detoxification by the nuclear pregnane X receptor.
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15736155 S.Choudhuri, and L.G.Valerio (2005).
Usefulness of studies on the molecular mechanism of action of herbals/botanicals: The case of St. John's wort.
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16922645 S.Ekins, S.Andreyev, A.Ryabov, E.Kirillov, E.A.Rakhmatulin, A.Bugrim, and T.Nikolskaya (2005).
Computational prediction of human drug metabolism.
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16456713 T.W.Loo, and D.M.Clarke (2005).
Recent progress in understanding the mechanism of P-glycoprotein-mediated drug efflux.
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16054614 X.C.Kretschmer, and W.S.Baldwin (2005).
CAR and PXR: xenosensors of endocrine disrupters?
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15864135 Y.P.Lim, C.H.Liu, L.J.Shyu, and J.D.Huang (2005).
Functional characterization of a novel polymorphism of pregnane X receptor, Q158K, in Chinese subjects.
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15288247 A.M.Davis, and R.J.Riley (2004).
Predictive ADMET studies, the challenges and the opportunities.
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15479477 C.Handschin, S.Blättler, A.Roth, R.Looser, M.Oscarson, M.R.Kaufmann, M.Podvinec, C.Gnerre, and U.A.Meyer (2004).
The evolution of drug-activated nuclear receptors: one ancestral gene diverged into two xenosensor genes in mammals.
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15246430 G.Benoit, M.Malewicz, and T.Perlmann (2004).
Digging deep into the pockets of orphan nuclear receptors: insights from structural studies.
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14996618 H.Gong, and W.Xie (2004).
Orphan nuclear receptors, PXR and LXR: new ligands and therapeutic potential.
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15610733 K.Suino, L.Peng, R.Reynolds, Y.Li, J.Y.Cha, J.J.Repa, S.A.Kliewer, and H.E.Xu (2004).
The nuclear xenobiotic receptor CAR: structural determinants of constitutive activation and heterodimerization.
  Mol Cell, 16, 893-905.
PDB code: 1xls
15610734 L.Shan, J.Vincent, J.S.Brunzelle, I.Dussault, M.Lin, I.Ianculescu, M.A.Sherman, B.M.Forman, and E.J.Fernandez (2004).
Structure of the murine constitutive androstane receptor complexed to androstenol: a molecular basis for inverse agonism.
  Mol Cell, 16, 907-917.
PDB code: 1xnx
15257299 M.A.Schumacher, M.C.Miller, and R.G.Brennan (2004).
Structural mechanism of the simultaneous binding of two drugs to a multidrug-binding protein.
  EMBO J, 23, 2923-2930.
PDB codes: 1qvt 1qvu
15610735 R.X.Xu, M.H.Lambert, B.B.Wisely, E.N.Warren, E.E.Weinert, G.M.Waitt, J.D.Williams, J.L.Collins, L.B.Moore, T.M.Willson, and J.T.Moore (2004).
A structural basis for constitutive activity in the human CAR/RXRalpha heterodimer.
  Mol Cell, 16, 919-928.
PDB codes: 1xv9 1xvp
15003246 S.Ekins (2004).
Predicting undesirable drug interactions with promiscuous proteins in silico.
  Drug Discov Today, 9, 276-285.  
15109949 W.Xie, H.Uppal, S.P.Saini, Y.Mu, J.M.Little, A.Radominska-Pandya, and M.A.Zemaitis (2004).
Orphan nuclear receptor-mediated xenobiotic regulation in drug metabolism.
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15059999 Z.Zhang, P.E.Burch, A.J.Cooney, R.B.Lanz, F.A.Pereira, J.Wu, R.A.Gibbs, G.Weinstock, and D.A.Wheeler (2004).
Genomic analysis of the nuclear receptor family: new insights into structure, regulation, and evolution from the rat genome.
  Genome Res, 14, 580-590.  
12536206 B.C.Kallenberger, J.D.Love, V.K.Chatterjee, and J.W.Schwabe (2003).
A dynamic mechanism of nuclear receptor activation and its perturbation in a human disease.
  Nat Struct Biol, 10, 136-140.  
12779079 C.A.Lamb, L.A.Helguero, V.Fabris, C.Lucas, A.A.Molinolo, and C.Lanari (2003).
Differential effects of raloxifene, tamoxifen and fulvestrant on a murine mammary carcinoma.
  Breast Cancer Res Treat, 79, 25-35.  
12520526 C.Carlberg (2003).
Molecular basis of the selective activity of vitamin D analogues.
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14633964 C.G.Dietrich, A.Geier, and R.P.Oude Elferink (2003).
ABC of oral bioavailability: transporters as gatekeepers in the gut.
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12605548 C.Liddle, and G.R.Robertson (2003).
Predicting inductive drug-drug interactions.
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12958591 C.Stehlin-Gaon, D.Willmann, D.Zeyer, S.Sanglier, A.Van Dorsselaer, J.P.Renaud, D.Moras, and R.Schüle (2003).
All-trans retinoic acid is a ligand for the orphan nuclear receptor ROR beta.
  Nat Struct Biol, 10, 820-825.
PDB codes: 1n4h 1nq7
12725856 D.McRee (2003).
Protecting against cocaine, heroin, and sarin gas.
  Chem Biol, 10, 295-297.  
12820970 E.P.Sablin, I.N.Krylova, R.J.Fletterick, and H.A.Ingraham (2003).
Structural basis for ligand-independent activation of the orphan nuclear receptor LRH-1.
  Mol Cell, 11, 1575-1585.
PDB code: 1pk5
14602925 J.Eeckhoute, B.Oxombre, P.Formstecher, P.Lefebvre, and B.Laine (2003).
Critical role of charged residues in helix 7 of the ligand binding domain in Hepatocyte Nuclear Factor 4alpha dimerisation and transcriptional activity.
  Nucleic Acids Res, 31, 6640-6650.  
12853622 J.M.Maglich, J.A.Caravella, M.H.Lambert, T.M.Willson, J.T.Moore, and L.Ramamurthy (2003).
The first completed genome sequence from a teleost fish (Fugu rubripes) adds significant diversity to the nuclear receptor superfamily.
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12526851 K.S.McKeegan, M.I.Borges-Walmsley, and A.R.Walmsley (2003).
The structure and function of drug pumps: an update.
  Trends Microbiol, 11, 21-29.  
12744492 K.Sachdeva, B.Yan, and C.O.Chichester (2003).
Lipopolysaccharide and cecal ligation/puncture differentially affect the subcellular distribution of the pregnane X receptor but consistently cause suppression of its target genes CYP3A.
  Shock, 19, 469-474.  
12670540 M.Choi, K.Yamamoto, T.Itoh, M.Makishima, D.J.Mangelsdorf, D.Moras, H.F.DeLuca, and S.Yamada (2003).
Interaction between vitamin D receptor and vitamin D ligands: two-dimensional alanine scanning mutational analysis.
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14585304 N.Landes, M.Birringer, and R.Brigelius-Flohé (2003).
Homologous metabolic and gene activating routes for vitamins E and K.
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12725862 S.Bencharit, C.L.Morton, J.L.Hyatt, P.Kuhn, M.K.Danks, P.M.Potter, and M.R.Redinbo (2003).
Crystal structure of human carboxylesterase 1 complexed with the Alzheimer's drug tacrine: from binding promiscuity to selective inhibition.
  Chem Biol, 10, 341-349.
PDB code: 1mx1
14636322 S.C.Nallani, T.A.Glauser, N.Hariparsad, K.Setchell, D.J.Buckley, A.R.Buckley, and P.B.Desai (2003).
Dose-dependent induction of cytochrome P450 (CYP) 3A4 and activation of pregnane X receptor by topiramate.
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12838268 S.J.Teague (2003).
Implications of protein flexibility for drug discovery.
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12799447 S.S.Auerbach, R.Ramsden, M.A.Stoner, C.Verlinde, C.Hassett, and C.J.Omiecinski (2003).
Alternatively spliced isoforms of the human constitutive androstane receptor.
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12767224 T.Ostberg, M.Jacobsson, A.Attersand, A.Mata de Urquiza, and L.Jendeberg (2003).
A triple mutant of the Drosophila ERR confers ligand-induced suppression of activity.
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12842037 Y.Li, M.H.Lambert, and H.E.Xu (2003).
Activation of nuclear receptors: a perspective from structural genomics.
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12068801 A.A.Neyfakh (2002).
Mystery of multidrug transporters: the answer can be simple.
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Regulation of cyp3a gene transcription by the pregnane x receptor.
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12387968 D.W.Nebert, and D.W.Russell (2002).
Clinical importance of the cytochromes P450.
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Pattern recognition and massively distributed computing.
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12101224 I.Dussault, M.Lin, K.Hollister, M.Fan, J.Termini, M.A.Sherman, and B.M.Forman (2002).
A structural model of the constitutive androstane receptor defines novel interactions that mediate ligand-independent activity.
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Functional consequences of cysteine modification in the ligand binding sites of peroxisome proliferator activated receptors by GW9662.
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12180910 M.A.Schumacher, and R.G.Brennan (2002).
Structural mechanisms of multidrug recognition and regulation by bacterial multidrug transcription factors.
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The PXR crystal structure: the end of the beginning.
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PXR, CAR and drug metabolism.
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12354121 T.Ostberg, G.Bertilsson, L.Jendeberg, A.Berkenstam, and J.Uppenberg (2002).
Identification of residues in the PXR ligand binding domain critical for species specific and constitutive activation.
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11983567 W.Xie, and R.M.Evans (2002).
Pharmaceutical use of mouse models humanized for the xenobiotic receptor.
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Activation of transcription through the ligand-binding pocket of the orphan nuclear receptor ultraspiracle.
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X-ray structure of the orphan nuclear receptor RORbeta ligand-binding domain in the active conformation.
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PDB code: 1k4w
11543861 E.M.Gillam (2001).
The PXR ligand-binding domain: how to be picky and promiscuous at the same time.
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11470577 R.N.Lawrence (2001).
News in brief.
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The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.