PDBsum entry 1m13

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protein ligands links
Transcription PDB id
Protein chain
273 a.a. *
Waters ×265
* Residue conservation analysis
PDB id:
Name: Transcription
Title: Crystal structure of the human pregane x receptor ligand binding domain in complex with hyperforin, a constituent of st. John's wort
Structure: Orphan nuclear receptor pxr. Chain: a. Fragment: includes ligand binding domain (residues 130- 434). Synonym: pregnane x receptor, orphan nuclear receptor par1, steroid and xenobiotic receptor, sxr. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: nr1i2 or pxr. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
Biol. unit: Dimer (from PQS)
2.15Å     R-factor:   0.212     R-free:   0.246
Authors: R.E.Watkins,J.M.Maglich,L.B.Moore,G.B.Wisely,S.M.Noble, P.R.Davis-Searles,M.H.Lambert,S.A.Kliewer,M.R.Redinbo
Key ref:
R.E.Watkins et al. (2003). 2.1 A crystal structure of human PXR in complex with the St. John's wort compound hyperforin. Biochemistry, 42, 1430-1438. PubMed id: 12578355 DOI: 10.1021/bi0268753
17-Jun-02     Release date:   04-Mar-03    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
O75469  (NR1I2_HUMAN) -  Nuclear receptor subfamily 1 group I member 2
434 a.a.
273 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: 10.1021/bi0268753 Biochemistry 42:1430-1438 (2003)
PubMed id: 12578355  
2.1 A crystal structure of human PXR in complex with the St. John's wort compound hyperforin.
R.E.Watkins, J.M.Maglich, L.B.Moore, G.B.Wisely, S.M.Noble, P.R.Davis-Searles, M.H.Lambert, S.A.Kliewer, M.R.Redinbo.
The nuclear xenobiotic receptor PXR is activated by a wide variety of clinically used drugs and serves as a master regulator of drug metabolism and excretion gene expression in mammals. St. John's wort is used widely in Europe and the United States to treat depression. This unregulated herbal remedy leads to dangerous drug-drug interactions, however, in patients taking oral contraceptives, antivirals, or immunosuppressants. Such interactions are caused by the activation of the human PXR by hyperforin, the psychoactive agent in St. John's wort. In this study, we show that hyperforin induces the expression of numerous drug metabolism and excretion genes in primary human hepatocytes. We present the 2.1 A crystal structure of hyperforin in complex with the ligand binding domain of human PXR. Hyperforin induces conformational changes in PXR's ligand binding pocket relative to structures of human PXR elucidated previously and increases the size of the pocket by 250 A(3). We find that the mutation of individual aromatic residues within the ligand binding cavity changes PXR's response to particular ligands. Taken together, these results demonstrate that PXR employs structural flexibility to expand the chemical space it samples and that the mutation of specific residues within the ligand binding pocket of PXR tunes the receptor's response to ligands.

Literature references that cite this PDB file's key reference

  PubMed id Reference
21059794 C.J.Omiecinski, J.P.Vanden Heuvel, G.H.Perdew, and J.M.Peters (2011).
Xenobiotic metabolism, disposition, and regulation by receptors: from biochemical phenomenon to predictors of major toxicities.
  Toxicol Sci, 120, S49-S75.  
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.  
20980920 W.C.Lau, T.D.Welch, T.Shields, M.Rubenfire, U.S.Tantry, and P.A.Gurbel (2011).
The effect of St John's Wort on the pharmacodynamic response of clopidogrel in hyporesponsive volunteers and patients: increased platelet inhibition by enhancement of CYP3A4 metabolic activity.
  J Cardiovasc Pharmacol, 57, 86-93.  
  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.  
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.  
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.  
  20558333 S.Kortagere, M.D.Krasowski, E.J.Reschly, M.Venkatesh, S.Mani, and S.Ekins (2010).
Evaluation of computational docking to identify pregnane X receptor agonists in the ToxCast database.
  Environ Health Perspect, 118, 1412-1417.  
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.  
  19240808 C.Zhou, S.Verma, and B.Blumberg (2009).
The steroid and xenobiotic receptor (SXR), beyond xenobiotic metabolism.
  Nucl Recept Signal, 7, e001.  
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.  
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.  
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.  
19688601 T.K.Chang (2009).
Activation of pregnane X receptor (PXR) and constitutive androstane receptor (CAR) by herbal medicines.
  AAPS J, 11, 590-601.  
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.  
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.  
18666802 J.K.Darby, D.J.Pasta, M.G.Wilson, and J.Herbert (2008).
Long-term therapeutic drug monitoring of risperidone and olanzapine identifies altered steady-state pharmacokinetics: a clinical, two-group, naturalistic study.
  Clin Drug Investig, 28, 553-564.  
  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.  
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.  
17378721 J.Kaput (2007).
Nutrigenomics--2006 update.
  Clin Chem Lab Med, 45, 279-287.  
17391074 J.Kaput, A.Perlina, B.Hatipoglu, A.Bartholomew, and Y.Nikolsky (2007).
Nutrigenomics: concepts and applications to pharmacogenomics and clinical medicine.
  Pharmacogenomics, 8, 369-390.  
17827782 K.Kojima, K.Nagata, T.Matsubara, and Y.Yamazoe (2007).
Broad but distinct role of pregnane x receptor on the expression of individual cytochrome p450s in human hepatocytes.
  Drug Metab Pharmacokinet, 22, 276-286.  
  17722645 R.P.Oude Elferink, and Waart (2007).
Transporters in the intestine limiting drug and toxin absorption.
  J Physiol Biochem, 63, 75-81.  
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.  
17284330 Y.E.Timsit, and M.Negishi (2007).
CAR and PXR: the xenobiotic-sensing receptors.
  Steroids, 72, 231-246.  
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.  
16766035 I.Cascorbi (2006).
Role of pharmacogenetics of ATP-binding cassette transporters in the pharmacokinetics of drugs.
  Pharmacol Ther, 112, 457-473.  
16982615 K.Mattison, J.S.Wilbur, M.So, and R.G.Brennan (2006).
Structure of FitAB from Neisseria gonorrhoeae bound to DNA reveals a tetramer of toxin-antitoxin heterodimers containing pin domains and ribbon-helix-helix motifs.
  J Biol Chem, 281, 37942-37951.
PDB codes: 2bsq 2h1c 2h1o
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.  
16640452 M.Wurglics, and M.Schubert-Zsilavecz (2006).
Hypericum perforatum: a 'modern' herbal antidepressant: pharmacokinetics of active ingredients.
  Clin Pharmacokinet, 45, 449-468.  
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.  
17061171 W.C.Lau, and P.A.Gurbel (2006).
Antiplatelet drug resistance and drug-drug interactions: Role of cytochrome P450 3A4.
  Pharm Res, 23, 2691-2708.  
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.  
16277761 J.Kaput, J.M.Ordovas, L.Ferguson, B.van Ommen, R.L.Rodriguez, L.Allen, B.N.Ames, K.Dawson, B.German, R.Krauss, W.Malyj, M.C.Archer, S.Barnes, A.Bartholomew, R.Birk, P.van Bladeren, K.J.Bradford, K.H.Brown, R.Caetano, D.Castle, R.Chadwick, S.Clarke, K.Clément, C.A.Cooney, D.Corella, I.B.Manica da Cruz, H.Daniel, T.Duster, S.O.Ebbesson, R.Elliott, S.Fairweather-Tait, J.Felton, M.Fenech, J.W.Finley, N.Fogg-Johnson, R.Gill-Garrison, M.J.Gibney, P.J.Gillies, J.A.Gustafsson, J.L.Hartman Iv, L.He, J.K.Hwang, J.P.Jais, Y.Jang, H.Joost, C.Junien, M.Kanter, W.A.Kibbe, B.Koletzko, B.R.Korf, K.Kornman, D.W.Krempin, D.Langin, D.R.Lauren, J.Ho Lee, G.A.Leveille, S.J.Lin, J.Mathers, M.Mayne, W.McNabb, J.A.Milner, P.Morgan, M.Muller, Y.Nikolsky, F.van der Ouderaa, T.Park, N.Pensel, F.Perez-Jimenez, K.Poutanen, M.Roberts, W.H.Saris, G.Schuster, A.N.Shelling, A.P.Simopoulos, S.Southon, E.S.Tai, B.Towne, P.Trayhurn, R.Uauy, W.J.Visek, C.Warden, R.Weiss, J.Wiencke, J.Winkler, G.L.Wolff, X.Zhao-Wilson, and J.D.Zucker (2005).
The case for strategic international alliances to harness nutritional genomics for public and personal health.
  Br J Nutr, 94, 623-632.  
15980170 L.Martínez, M.T.Sonoda, P.Webb, J.D.Baxter, M.S.Skaf, and I.Polikarpov (2005).
Molecular dynamics simulations reveal multiple pathways of ligand dissociation from thyroid hormone receptors.
  Biophys J, 89, 2011-2023.  
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.  
15593112 M.Gartner, T.Müller, J.C.Simon, A.Giannis, and J.P.Sleeman (2005).
Aristoforin, a novel stable derivative of hyperforin, is a potent anticancer agent.
  Chembiochem, 6, 171-177.  
15642254 M.Newcomer (2005).
A response to reimportation.
  Structure, 13, 1-2.  
16011469 N.F.Shay, and W.J.Banz (2005).
Regulation of gene transcription by botanicals: novel regulatory mechanisms.
  Annu Rev Nutr, 25, 297-315.  
15858847 R.G.Tirona, and R.B.Kim (2005).
Nuclear receptors and drug disposition gene regulation.
  J Pharm Sci, 94, 1169-1186.  
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.
  J Biochem Mol Toxicol, 19, 1.  
16922645 S.Ekins, S.Andreyev, A.Ryabov, E.Kirillov, E.A.Rakhmatulin, A.Bugrim, and T.Nikolskaya (2005).
Computational prediction of human drug metabolism.
  Expert Opin Drug Metab Toxicol, 1, 303-324.  
16220113 S.Krusekopf, and I.Roots (2005).
St. John's wort and its constituent hyperforin concordantly regulate expression of genes encoding enzymes involved in basic cellular pathways.
  Pharmacogenet Genomics, 15, 817-829.  
15466465 B.Sandler, P.Webb, J.W.Apriletti, B.R.Huber, M.Togashi, S.T.Cunha Lima, S.Juric, S.Nilsson, R.Wagner, R.J.Fletterick, and J.D.Baxter (2004).
Thyroxine-thyroid hormone receptor interactions.
  J Biol Chem, 279, 55801-55808.
PDB codes: 1xzx 1y0x
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.
  Nucl Recept, 2, 7.  
15246430 G.Benoit, M.Malewicz, and T.Perlmann (2004).
Digging deep into the pockets of orphan nuclear receptors: insights from structural studies.
  Trends Cell Biol, 14, 369-376.  
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.  
14498828 F.M.Sladek (2003).
Nuclear receptors as drug targets: new developments in coregulators, orphan receptors and major therapeutic areas.
  Expert Opin Ther Targets, 7, 679-684.  
12819202 M.Färnegårdh, T.Bonn, S.Sun, J.Ljunggren, H.Ahola, A.Wilhelmsson, J.A.Gustafsson, and M.Carlquist (2003).
The three-dimensional structure of the liver X receptor beta reveals a flexible ligand-binding pocket that can accommodate fundamentally different ligands.
  J Biol Chem, 278, 38821-38828.
PDB codes: 1pq6 1pq9 1pqc
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.