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PDBsum entry 1osv

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protein ligands Protein-protein interface(s) links
DNA binding protein PDB id
1osv
Jmol
Contents
Protein chains
229 a.a. *
12 a.a. *
Ligands
CHC ×2
Waters ×152
* Residue conservation analysis
PDB id:
1osv
Name: DNA binding protein
Title: Structural basis for bile acid binding and activation of the nuclear receptor fxr
Structure: Bile acid receptor. Chain: a, b. Fragment: ligand binding domain (fxr-lbd). Synonym: farnesoid x-activated receptor, farnesol receptor hrr-1, retinoid x receptor-interacting protein 14, rxr- interacting protein 14. Engineered: yes. Nuclear receptor coactivator 2. Chain: c, d, e.
Source: Rattus norvegicus. Norway rat. Organism_taxid: 10116. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Synthetic: yes. Other_details: the coactivator peptide was synthesized. The sequence of the grip is naturally found in rattus norvegicus (norway rat).
Biol. unit: Trimer (from PQS)
Resolution:
2.50Å     R-factor:   0.242     R-free:   0.276
Authors: L.Z.Mi,S.Devarakonda,J.M.Harp,Q.Han,R.Pellicciari, T.M.Willson,S.Khorasanizadeh,F.Rastinejad
Key ref:
L.Z.Mi et al. (2003). Structural basis for bile acid binding and activation of the nuclear receptor FXR. Mol Cell, 11, 1093-1100. PubMed id: 12718893 DOI: 10.1016/S1097-2765(03)00112-6
Date:
20-Mar-03     Release date:   23-Mar-04    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
Q62735  (NR1H4_RAT) -  Bile acid receptor
Seq:
Struc:
469 a.a.
229 a.a.*
Protein chains
Pfam   ArchSchema ?
Q61026  (NCOA2_MOUSE) -  Nuclear receptor coactivator 2
Seq:
Struc:
 
Seq:
Struc:
 
Seq:
Struc:
1462 a.a.
12 a.a.
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 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  

 

 
DOI no: 10.1016/S1097-2765(03)00112-6 Mol Cell 11:1093-1100 (2003)
PubMed id: 12718893  
 
 
Structural basis for bile acid binding and activation of the nuclear receptor FXR.
L.Z.Mi, S.Devarakonda, J.M.Harp, Q.Han, R.Pellicciari, T.M.Willson, S.Khorasanizadeh, F.Rastinejad.
 
  ABSTRACT  
 
The nuclear receptor FXR is the sensor of physiological levels of enterohepatic bile acids, the end products of cholesterol catabolism. Here we report crystal structures of the FXR ligand binding domain in complex with coactivator peptide and two different bile acids. An unusual A/B ring juncture, a feature associated with bile acids and no other steroids, provides ligand discrimination and triggers a pi-cation switch that activates FXR. Helix 12, the activation function 2 of the receptor, adopts the agonist conformation and stabilizes coactivator peptide binding. FXR is able to interact simultaneously with two coactivator motifs, providing a mechanism for enhanced binding of coactivators through intermolecular contacts between their LXXLL sequences. These FXR complexes provide direct insights into the design of therapeutic bile acids for treatment of hyperlipidemia and cholestasis.
 
  Selected figure(s)  
 
Figure 1.
Figure 1. Overall Views of FXR and Its Ligand Interactions(A) Perpendicular views of the FXR LBD (purple) from complex b of the 6ECDCA complex. Helix 12 of the receptor is shown in yellow, the GRIP-1 peptides are shown in blue and red, and 6ECDCA is shown in green.(B) Stereo view of a simulated annealing omit electron density (Fo-Fc) map showing the bound 6ECDCA. The ligand was excluded in map calculation.(C) Schematic representation of the FXR/6ECDCA interactions. Dotted red lines indicate hydrogen bonds; dotted blue lines indicate van der Waals contacts.
Figure 2.
Figure 2. The Activation Mechanism of FXR(A) 6ECDCA and 3-deoxyCDCA interactions with the activation switch of FXR. Shown is the superposition of their two crystal structures in the vicinity of the ligand and residues His444 and Trp466.(B) The binding of GRIP-1 NID-3 coactivator peptide to FXR as a function of increasing 3-deoxyCDCA (black triangles) and CDCA (red circles).
 
  The above figures are reprinted by permission from Cell Press: Mol Cell (2003, 11, 1093-1100) copyright 2003.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
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.  
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.  
20723571 L.Jin, and Y.Li (2010).
Structural and functional insights into nuclear receptor signaling.
  Adv Drug Deliv Rev, 62, 1218-1226.  
20148675 P.Huang, V.Chandra, and F.Rastinejad (2010).
Structural overview of the nuclear receptor superfamily: insights into physiology and therapeutics.
  Annu Rev Physiol, 72, 247-272.  
20372994 S.Mukherjee, and S.Mani (2010).
Orphan nuclear receptors as targets for drug development.
  Pharm Res, 27, 1439-1468.  
18670431 C.Thomas, R.Pellicciari, M.Pruzanski, J.Auwerx, and K.Schoonjans (2008).
Targeting bile-acid signalling for metabolic diseases.
  Nat Rev Drug Discov, 7, 678-693.  
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.  
18785728 P.Cozzini, G.E.Kellogg, F.Spyrakis, D.J.Abraham, G.Costantino, A.Emerson, F.Fanelli, H.Gohlke, L.A.Kuhn, G.M.Morris, M.Orozco, T.A.Pertinhez, M.Rizzi, and C.A.Sotriffer (2008).
Target flexibility: an emerging consideration in drug discovery and design.
  J Med Chem, 51, 6237-6255.  
18391212 S.M.Soisson, G.Parthasarathy, A.D.Adams, S.Sahoo, A.Sitlani, C.Sparrow, J.Cui, and J.W.Becker (2008).
Identification of a potent synthetic FXR agonist with an unexpected mode of binding and activation.
  Proc Natl Acad Sci U S A, 105, 5337-5342.
PDB code: 3bej
18798693 S.W.Kruse, K.Suino-Powell, X.E.Zhou, J.E.Kretschman, R.Reynolds, C.Vonrhein, Y.Xu, L.Wang, S.Y.Tsai, M.J.Tsai, and H.E.Xu (2008).
Identification of COUP-TFII orphan nuclear receptor as a retinoic acid-activated receptor.
  PLoS Biol, 6, e227.
PDB code: 3cjw
18668687 T.Frankenberg, T.Miloh, F.Y.Chen, M.Ananthanarayanan, A.Q.Sun, N.Balasubramaniyan, I.Arias, K.D.Setchell, F.J.Suchy, and B.L.Shneider (2008).
The membrane protein ATPase class I type 8B member 1 signals through protein kinase C zeta to activate the farnesoid X receptor.
  Hepatology, 48, 1896-1905.  
17910058 T.Zhang, J.H.Zhou, L.W.Shi, R.X.Zhu, and M.B.Chen (2008).
Molecular dynamics simulation study for LRH-1: interaction with fragments of SHP and function of phospholipid ligand.
  Proteins, 70, 1527-1539.  
18825165 Y.D.Wang, W.D.Chen, D.D.Moore, and W.Huang (2008).
FXR: a metabolic regulator and cell protector.
  Cell Res, 18, 1087-1095.  
17601774 H.C.Shea, D.D.Head, K.D.Setchell, and D.W.Russell (2007).
Analysis of HSD3B7 knockout mice reveals that a 3alpha-hydroxyl stereochemistry is required for bile acid function.
  Proc Natl Acad Sci U S A, 104, 11526-11533.  
17058234 J.Trottier, M.Verreault, S.Grepper, D.Monté, J.Bélanger, J.Kaeding, P.Caron, T.T.Inaba, and O.Barbier (2006).
Human UDP-glucuronosyltransferase (UGT)1A3 enzyme conjugates chenodeoxycholic acid in the liver.
  Hepatology, 44, 1158-1170.  
15542861 F.A.Klein, R.A.Atkinson, N.Potier, D.Moras, and J.Cavarelli (2005).
Biochemical and NMR mapping of the interface between CREB-binding protein and ligand binding domains of nuclear receptor: beyond the LXXLL motif.
  J Biol Chem, 280, 5682-5692.  
15809296 J.A.Carmichael, M.C.Lawrence, L.D.Graham, P.A.Pilling, V.C.Epa, L.Noyce, G.Lovrecz, D.A.Winkler, A.Pawlak-Skrzecz, R.E.Eaton, G.N.Hannan, and R.J.Hill (2005).
The X-ray structure of a hemipteran ecdysone receptor ligand-binding domain: comparison with a lepidopteran ecdysone receptor ligand-binding domain and implications for insecticide design.
  J Biol Chem, 280, 22258-22269.
PDB code: 1z5x
15709961 K.W.Nettles, and G.L.Greene (2005).
Ligand control of coregulator recruitment to nuclear receptors.
  Annu Rev Physiol, 67, 309-333.  
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.
  J Cell Biochem, 94, 917-943.  
15558556 T.Shiraki, T.S.Kodama, H.Jingami, and N.Kamiya (2005).
Rational discovery of a novel interface for a coactivator in the peroxisome proliferator-activated receptor gamma: theoretical implications of impairment in type 2 diabetes mellitus.
  Proteins, 58, 418-425.  
14992717 C.K.Glass, D.P.McDonnell, and E.Jensen (2004).
The jensen symposium; a tribute to a pioneer in the field of nuclear receptor biology.
  Mol Cell, 13, 459-467.  
15703646 M.Trauner, and J.L.Boyer (2004).
Cholestatic syndromes.
  Curr Opin Gastroenterol, 20, 220-230.  
15521018 S.Fiorucci, E.Antonelli, G.Rizzo, B.Renga, A.Mencarelli, L.Riccardi, S.Orlandi, R.Pellicciari, and A.Morelli (2004).
The nuclear receptor SHP mediates inhibition of hepatic stellate cells by FXR and protects against liver fibrosis.
  Gastroenterology, 127, 1497-1512.  
15330745 T.Claudel, E.Sturm, F.Kuipers, and B.Staels (2004).
The farnesoid X receptor: a novel drug target?
  Expert Opin Investig Drugs, 13, 1135-1148.  
12912852 A.F.Hofmann (2003).
Inappropriate ileal conservation of bile acids in cholestatic liver disease: homeostasis gone awry.
  Gut, 52, 1239-1241.  
14592980 S.Devarakonda, J.M.Harp, Y.Kim, A.Ozyhar, and F.Rastinejad (2003).
Structure of the heterodimeric ecdysone receptor DNA-binding complex.
  EMBO J, 22, 5827-5840.
PDB codes: 1r0n 1r0o
12736258 S.Williams, R.K.Bledsoe, J.L.Collins, S.Boggs, M.H.Lambert, A.B.Miller, J.Moore, D.D.McKee, L.Moore, J.Nichols, D.Parks, M.Watson, B.Wisely, and T.M.Willson (2003).
X-ray crystal structure of the liver X receptor beta ligand binding domain: regulation by a histidine-tryptophan switch.
  J Biol Chem, 278, 27138-27143.
PDB code: 1p8d
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.