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PDBsum entry 1p8d

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protein ligands Protein-protein interface(s) links
Membrane protein/protein binding PDB id
1p8d
Jmol PyMol
Contents
Protein chains
240 a.a. *
16 a.a. *
13 a.a. *
Ligands
CO1 ×2
Waters ×99
* Residue conservation analysis
PDB id:
1p8d
Name: Membrane protein/protein binding
Title: X-ray crystal structure of lxr ligand binding domain with 24 epoxycholesterol
Structure: Oxysterols receptor lxr-beta. Chain: a, b. Fragment: liver x receptor beta ligand binding domain (resi 461). Synonym: liver x receptor beta, nuclear orphan receptor lxr ubiquitously-expressed nuclear receptor, nuclear receptor n engineered: yes. Nuclear receptor coactivator 1 isoform 3. Chain: c, d.
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: nr1h2 or lxrb or unr or ner. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Other_details: pepetide synthesis
Biol. unit: Dimer (from PQS)
Resolution:
2.80Å     R-factor:   0.214     R-free:   0.277
Authors: S.Williams,R.K.Bledsoe,J.L.Collins,S.Boggs,M.H.Lambert,A.B.M J.Moore,D.D.Mckee,L.Moore,J.Nichols,D.Parks,M.Watson,B.Wise T.M.Willson
Key ref:
S.Williams et al. (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. PubMed id: 12736258 DOI: 10.1074/jbc.M302260200
Date:
06-May-03     Release date:   08-Jul-03    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P55055  (NR1H2_HUMAN) -  Oxysterols receptor LXR-beta
Seq:
Struc:
460 a.a.
240 a.a.
Protein chain
Pfam   ArchSchema ?
Q15788  (NCOA1_HUMAN) -  Nuclear receptor coactivator 1
Seq:
Struc:
 
Seq:
Struc:
 
Seq:
Struc:
1441 a.a.
16 a.a.
Protein chain
Pfam   ArchSchema ?
Q15788  (NCOA1_HUMAN) -  Nuclear receptor coactivator 1
Seq:
Struc:
 
Seq:
Struc:
 
Seq:
Struc:
1441 a.a.
13 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: Chains C, D: 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     2 terms  

 

 
    Added reference    
 
 
DOI no: 10.1074/jbc.M302260200 J Biol Chem 278:27138-27143 (2003)
PubMed id: 12736258  
 
 
X-ray crystal structure of the liver X receptor beta ligand binding domain: regulation by a histidine-tryptophan switch.
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, T.M.Willson.
 
  ABSTRACT  
 
The x-ray crystal structures of the human liver X receptor beta ligand binding domain complexed to sterol and nonsterol agonists revealed a perpendicular histidinetryptophan switch that holds the receptor in its active conformation. Hydrogen bonding interactions with the ligand act to position the His-435 imidazole ring against the Trp-457 indole ring, allowing an electrostatic interaction that holds the AF2 helix in the active position. The neutral oxysterol 24(S),25-epoxycholesterol accepts a hydrogen bond from His-435 that positions the imidazole ring of the histidine above the pyrrole ring of the tryptophan. In contrast, the acidic T0901317 hydroxyl group makes a shorter hydrogen bond with His-435 that pulls the imidazole over the electron-rich benzene ring of the tryptophan, possibly strengthening the electrostatic interaction. Point mutagenesis of Trp-457 supports the observation that the ligand-histidine-tryptophan coupling is different between the two ligands. The lipophilic liver X receptor ligand-binding pocket is larger than the corresponding steroid hormone receptors, which allows T0901317 to adopt two distinct conformations. These results provide a molecular basis for liver X receptor activation by a wide range of endogenous neutral and acidic ligands.
 
  Selected figure(s)  
 
Figure 2.
FIG. 2. Structure of the LXR LBD. LXR /eCH/SRC1 crystallized as a dimer with an orientation and dimer interface similar to that seen with other nuclear receptors. Helices in the two LXR monomers are shown in red and pink, whereas -strands are yellow, loops are cyan, and the SRC1 helix is magenta. LXR helices 1-10 and AF2 are labeled H1-H10 and HAF2. Nitrogen, oxygen, and hydrogen atoms are colored blue, red, and white, respectively, whereas carbon atoms are colored green, yellow, cyan, cyan, and yellow in eCH, Glu-281, Arg-319, His-435, and Trp-457, respectively. The same dimer orientation was obtained in the T1317 complex (not shown).
Figure 3.
FIG. 3. LXR ligand binding pocket. The ligand and amino acid residues forming the ligand binding pocket are shown in stick representation with nitrogen and oxygen atoms colored blue and red, respectively. Ligand and amino acid carbons are green and yellow, respectively. The ligand is highlighted in bold. Key residues in the binding site are identified by residue number and are also highlighted in bold. a, the LXR ligand binding pocket complexed to eCH. b, the LXR ligand binding pocket complexed to T1317 showing the gauche conformation of the ligand. c, the LXR ligand binding pocket complexed to T1317 showing the anti conformation of the ligand.
 
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2003, 278, 27138-27143) copyright 2003.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20419060 A.Majdalawieh, and H.S.Ro (2010).
PPARgamma1 and LXRalpha face a new regulator of macrophage cholesterol homeostasis and inflammatory responsiveness, AEBP1.
  Nucl Recept Signal, 8, e004.  
20711621 A.N.Steere, S.L.Byrne, N.D.Chasteen, V.C.Smith, R.T.MacGillivray, and A.B.Mason (2010).
Evidence that His349 acts as a pH-inducible switch to accelerate receptor-mediated iron release from the C-lobe of human transferrin.
  J Biol Inorg Chem, 15, 1341-1352.  
19933273 E.H.Anthonisen, L.Berven, S.Holm, M.Nygård, H.I.Nebb, and L.M.Grønning-Wang (2010).
Nuclear receptor liver X receptor is O-GlcNAc-modified in response to glucose.
  J Biol Chem, 285, 1607-1615.  
20655343 I.G.Schulman (2010).
Nuclear receptors as drug targets for metabolic disease.
  Adv Drug Deliv Rev, 62, 1307-1315.  
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.  
20817759 R.Goyanka, S.Das, H.H.Samuels, and T.Cardozo (2010).
Nuclear receptor engineering based on novel structure activity relationships revealed by farnesyl pyrophosphate.
  Protein Eng Des Sel, 23, 809-815.  
20372994 S.Mukherjee, and S.Mani (2010).
Orphan nuclear receptors as targets for drug development.
  Pharm Res, 27, 1439-1468.  
18275080 A.Beautrait, A.S.Karaboga, M.Souchet, and B.Maigret (2008).
Induced fit in liver X receptor beta: a molecular dynamics-based investigation.
  Proteins, 72, 873-882.  
18172702 A.Beautrait, V.Leroux, M.Chavent, L.Ghemtio, M.D.Devignes, M.Smaïl-Tabbone, W.Cai, X.Shao, G.Moreau, P.Bladon, J.Yao, and B.Maigret (2008).
Multiple-step virtual screening using VSM-G: overview and validation of fast geometrical matching enrichment.
  J Mol Model, 14, 135-148.  
18723776 D.Peng, R.A.Hiipakka, Q.Dai, J.Guo, C.A.Reardon, G.S.Getz, and S.Liao (2008).
Antiatherosclerotic effects of a novel synthetic tissue-selective steroidal liver X receptor agonist in low-density lipoprotein receptor-deficient mice.
  J Pharmacol Exp Ther, 327, 332-342.  
18395439 E.J.Reschly, N.Ai, W.J.Welsh, S.Ekins, L.R.Hagey, and M.D.Krasowski (2008).
Ligand specificity and evolution of liver X receptors.
  J Steroid Biochem Mol Biol, 110, 83-94.  
18221307 N.Malini, H.Rajesh, P.Berwal, S.Phukan, and V.N.Balaji (2008).
Analysis of crystal structures of LXRbeta in relation to plasticity of the ligand-binding domain upon ligand binding.
  Chem Biol Drug Des, 71, 140-154.  
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
18389516 Y.Hashimoto (2008).
Thalidomide as a multi-template for development of biologically active compounds.
  Arch Pharm (Weinheim), 341, 536-547.  
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
16819881 A.Q.Hassan, and J.T.Koh (2006).
A functionally orthogonal ligand-receptor pair created by targeting the allosteric mechanism of the thyroid hormone receptor.
  J Am Chem Soc, 128, 8868-8874.  
16892386 J.T.Moore, J.L.Collins, and K.H.Pearce (2006).
The nuclear receptor superfamily and drug discovery.
  ChemMedChem, 1, 504-523.  
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.  
16136145 Y.J.Im, S.Raychaudhuri, W.A.Prinz, and J.H.Hurley (2005).
Structural mechanism for sterol sensing and transport by OSBP-related proteins.
  Nature, 437, 154-158.
PDB codes: 1zht 1zhw 1zhx 1zhy 1zhz 1zi7
15016376 A.I.Shulman, C.Larson, D.J.Mangelsdorf, and R.Ranganathan (2004).
Structural determinants of allosteric ligand activation in RXR heterodimers.
  Cell, 116, 417-429.  
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.  
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
15052330 V.M.Olkkonen, and T.P.Levine (2004).
Oxysterol binding proteins: in more than one place at one time?
  Biochem Cell Biol, 82, 87-98.  
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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