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PDBsum entry 1xvp

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protein ligands Protein-protein interface(s) links
DNA binding protein PDB id
1xvp
Jmol PyMol
Contents
Protein chains
232 a.a. *
246 a.a. *
12 a.a. *
12 a.a. *
Ligands
HIS-LYS-ILE-LEU-
HIS-ARG-LEU-LEU-
GLN-GLU
F15 ×2
CID
Waters ×98
* Residue conservation analysis
PDB id:
1xvp
Name: DNA binding protein
Title: Crystal structure of car/rxr heterodimer bound with src1 pep fatty acid and citco
Structure: Retinoic acid receptor rxr-alpha. Chain: a, c. Fragment: lbd domain. Synonym: constitutive androstane receptor, car, orphan nucl receptor mb67. Engineered: yes. Orphan nuclear receptor nr1i3. Chain: b, d. Fragment: lbd domain.
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: nr1i3, car. Expressed in: escherichia coli. Expression_system_taxid: 562. Gene: rxra, nr2b1. Synthetic: yes. Other_details: chemically synthesized
Biol. unit: Octamer (from PQS)
Resolution:
2.60Å     R-factor:   0.180     R-free:   0.234
Authors: R.X.Xu,M.H.Lambert,B.B.Wisely,E.N.Warren,E.E.Weinert,G.M.Wai J.D.Williams,L.B.Moore,T.M.Willson,J.T.Moore
Key ref:
R.X.Xu et al. (2004). A structural basis for constitutive activity in the human CAR/RXRalpha heterodimer. Mol Cell, 16, 919-928. PubMed id: 15610735 DOI: 10.1016/j.molcel.2004.11.042
Date:
28-Oct-04     Release date:   28-Dec-04    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P19793  (RXRA_HUMAN) -  Retinoic acid receptor RXR-alpha
Seq:
Struc:
462 a.a.
232 a.a.
Protein chains
Pfam   ArchSchema ?
Q14994  (NR1I3_HUMAN) -  Nuclear receptor subfamily 1 group I member 3
Seq:
Struc:
352 a.a.
246 a.a.
Protein chain
No UniProt id for this chain
Struc: 12 a.a.
Protein chains
No UniProt id for this chain
Struc: 12 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: Chains F, G, H: E.C.2.3.1.48  - Histone acetyltransferase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Acetyl-CoA + [histone] = CoA + acetyl-[histone]
Acetyl-CoA
+ [histone]
= CoA
+ acetyl-[histone]
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 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     4 terms  

 

 
    Added reference    
 
 
DOI no: 10.1016/j.molcel.2004.11.042 Mol Cell 16:919-928 (2004)
PubMed id: 15610735  
 
 
A structural basis for constitutive activity in the human CAR/RXRalpha heterodimer.
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, J.T.Moore.
 
  ABSTRACT  
 
The X-ray crystal structure of the human constitutive androstane receptor (CAR, NR1I3)/retinoid X receptor alpha (RXRalpha, NR2B1) heterodimer sheds light on the mechanism of ligand-independent activation of transcription by nuclear receptors. CAR contains a single-turn Helix X that restricts the conformational freedom of the C-terminal AF2 helix, favoring the active state of the receptor. Helix X and AF2 sit atop four amino acids that shield the CAR ligand binding pocket. A fatty acid ligand was identified in the RXRalpha binding pocket. The endogenous RXRalpha ligand, combined with stabilizing interactions from the heterodimer interface, served to hold RXRalpha in an active conformation. The structure suggests that upon translocation, CAR/RXRalpha heterodimers are preorganized in an active conformation in cells such that they can regulate transcription of target genes. Insights into the molecular basis of CAR constitutive activity can be exploited in the design of inverse agonists as drugs for treatment of obesity.
 
  Selected figure(s)  
 
Figure 1.
Figure 1. CAR/RXRα Heterodimer Structure in the Complex with CITCO, Fatty Acid, and SRC-1 Peptides(A) Ribbon diagram of the human CAR/RXRα heterodimer complex with two SRC-1 peptides. CITCO is docked in the CAR ligand binding site as described in the text. The SRC-1 peptides are in magenta. The 3[10] helixes of CAR and RXRα are colored blue. The AF2 helices are colored in red. Helix X (H-X) is colored in gold. H7 and H10 are annotated. CITCO in CAR and the endogenous fatty acid in RXRα are shown in space-filling representation colored by atom type: oxygen is red, nitrogen is blue, sulfur is yellow, and carbon is green.(B) 90° rotation of the heterodimer viewed from the bottom of H10.
Figure 2.
Figure 2. Structural Features of the CAR/RXRα Heterodimer(A) Ribbon diagrams of the C terminus of CAR (blue), VDR (yellow), and PXR (green). In CAR, Helix X is colored in gold, and the AF2 helix is in red. The SRC-1 peptide is colored magenta. K195 from CAR that interacts with the C-terminal carboxylate is shown in sick representation colored by atom type.(B) Ribbon diagram of CAR with Helix X in gold and the AF2 helix in red. Helix H3 has been deleted for clarity. The four barrier residues are shown with carbon atoms colored yellow. Key residues from Helix X and the AF2 helix that sit on the barrier are colored with gold and red, respectively. CITCO is shown in space-filling representation colored by atom type.(C) Ribbon diagrams CAR (blue) and PPARγ (green) showing the difference in the bowing of H7. The linear H7 in CAR is shown in dark blue.(D) Ribbon diagram showing the interaction of T462 from RXRa with H332 for CAR H10 and N235 from H10. CAR is colored in blue. RXRα is colored in yellow with the AF2 C-terminal extension in red.
 
  The above figures are reprinted by permission from Cell Press: Mol Cell (2004, 16, 919-928) copyright 2004.  
  Figures were selected by the author.  

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.  
21227907 J.G.DeKeyser, E.M.Laurenzana, E.C.Peterson, T.Chen, and C.J.Omiecinski (2011).
Selective phthalate activation of naturally occurring human constitutive androstane receptor splice variants and the pregnane x receptor.
  Toxicol Sci, 120, 381-391.  
21292004 S.Surapureddi, R.Rana, and J.A.Goldstein (2011).
NCOA6 differentially regulates the expression of the CYP2C9 and CYP3A4 genes.
  Pharmacol Res, 63, 405-413.  
20113149 H.Li, and H.Wang (2010).
Activation of xenobiotic receptors: driving into the nucleus.
  Expert Opin Drug Metab Toxicol, 6, 409-426.  
  20957188 J.T.Bridgham, G.N.Eick, C.Larroux, K.Deshpande, M.J.Harms, M.E.Gauthier, E.A.Ortlund, B.M.Degnan, and J.W.Thornton (2010).
Protein evolution by molecular tinkering: diversification of the nuclear receptor superfamily from a ligand-dependent ancestor.
  PLoS Biol, 8, 0.  
20723571 L.Jin, and Y.Li (2010).
Structural and functional insights into nuclear receptor signaling.
  Adv Drug Deliv Rev, 62, 1218-1226.  
20372994 S.Mukherjee, and S.Mani (2010).
Orphan nuclear receptors as targets for drug development.
  Pharm Res, 27, 1439-1468.  
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.  
19211671 J.G.DeKeyser, M.C.Stagliano, S.S.Auerbach, K.S.Prabhu, A.D.Jones, and C.J.Omiecinski (2009).
Di(2-ethylhexyl) phthalate is a highly potent agonist for the human constitutive androstane receptor splice variant CAR2.
  Mol Pharmacol, 75, 1005-1013.  
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.  
20052392 L.S.Chan, and R.A.Wells (2009).
Cross-Talk between PPARs and the Partners of RXR: A Molecular Perspective.
  PPAR Res, 2009, 925309.  
19858220 S.Mutoh, M.Osabe, K.Inoue, R.Moore, L.Pedersen, L.Perera, Y.Rebolloso, T.Sueyoshi, and M.Negishi (2009).
Dephosphorylation of threonine 38 is required for nuclear translocation and activation of human xenobiotic receptor CAR (NR1I3).
  J Biol Chem, 284, 34785-34792.  
19126866 T.Iwema, A.Chaumot, R.A.Studer, M.Robinson-Rechavi, I.M.Billas, D.Moras, V.Laudet, and F.Bonneton (2009).
Structural and evolutionary innovation of the heterodimerization interface between USP and the ecdysone receptor ECR in insects.
  Mol Biol Evol, 26, 753-768.  
17596960 G.M.Waitt, R.Xu, G.B.Wisely, and J.D.Williams (2008).
Automated in-line gel filtration for native state mass spectrometry.
  J Am Soc Mass Spectrom, 19, 239-245.  
18154449 J.K.Lamba (2008).
Pharmacogenetics of the constitutive androstane receptor.
  Pharmacogenomics, 9, 71-83.  
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.  
17174397 A.C.Bainy (2007).
Nuclear receptors and susceptibility to chemical exposure in aquatic organisms.
  Environ Int, 33, 571-575.  
17848566 C.Browning, E.Martin, C.Loch, J.M.Wurtz, D.Moras, R.H.Stote, A.P.Dejaegere, and I.M.Billas (2007).
Critical role of desolvation in the binding of 20-hydroxyecdysone to the ecdysone receptor.
  J Biol Chem, 282, 32924-32934.
PDB code: 2r40
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.  
17936931 L.M.Tompkins, and A.D.Wallace (2007).
Mechanisms of cytochrome P450 induction.
  J Biochem Mol Toxicol, 21, 176-181.  
17355985 M.A.Stoner, S.S.Auerbach, S.M.Zamule, S.C.Strom, and C.J.Omiecinski (2007).
Transactivation of a DR-1 PPRE by a human constitutive androstane receptor variant expressed from internal protein translation start sites.
  Nucleic Acids Res, 35, 2177-2190.  
17284330 Y.E.Timsit, and M.Negishi (2007).
CAR and PXR: the xenobiotic-sensing receptors.
  Steroids, 72, 231-246.  
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.  
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.  
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.  
17163485 X.Chen, S.Maiti, J.Zhang, and G.Chen (2006).
Nuclear receptor interactions in methotrexate induction of human dehydroepiandrosterone sulfotransferase (hSULT2A1).
  J Biochem Mol Toxicol, 20, 309-317.  
16054039 D.D.Moore (2005).
CAR: three new models for a problem child.
  Cell Metab, 1, 6-8.  
15888456 F.Molnár, M.Matilainen, and C.Carlberg (2005).
Structural determinants of the agonist-independent association of human peroxisome proliferator-activated receptors with coactivators.
  J Biol Chem, 280, 26543-26556.  
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.  
15994320 P.Gu, D.H.Morgan, M.Sattar, X.Xu, R.Wagner, M.Raviscioni, O.Lichtarge, and A.J.Cooney (2005).
Evolutionary trace-based peptides identify a novel asymmetric interaction that mediates oligomerization in nuclear receptors.
  J Biol Chem, 280, 31818-31829.  
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.  
16054614 X.C.Kretschmer, and W.S.Baldwin (2005).
CAR and PXR: xenosensors of endocrine disrupters?
  Chem Biol Interact, 155, 111-128.  
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
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.

 

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