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PDBsum entry 1upw

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protein ligands links
Receptor PDB id
1upw
Jmol
Contents
Protein chain
232 a.a. *
Ligands
444
* Residue conservation analysis
PDB id:
1upw
Name: Receptor
Title: Crystal structure of the human liver x receptor beta ligand binding domain in complex with a synthetic agonist
Structure: Oxysterols receptor lxr-beta. Chain: a. Fragment: ligand binding domain, residues 209-461. Synonym: liver x receptor beta, nuclear orphan, receptor lxr-beta, ubiquitously-expressed nuclear receptor, nuclear receptor ner. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 511693. Expression_system_variant: de3.
Resolution:
2.4Å     R-factor:   0.250     R-free:   0.295
Authors: S.Hoerer,A.Schmid,A.Heckel,R.M.Budzinski,H.Nar
Key ref:
S.Hoerer et al. (2003). Crystal structure of the human liver X receptor beta ligand-binding domain in complex with a synthetic agonist. J Mol Biol, 334, 853-861. PubMed id: 14643652 DOI: 10.1016/j.jmb.2003.10.033
Date:
13-Oct-03     Release date:   20-Oct-04    
PROCHECK
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 Headers
 References

Protein chain
Pfam   ArchSchema ?
P55055  (NR1H2_HUMAN) -  Oxysterols receptor LXR-beta
Seq:
Struc:
460 a.a.
232 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     4 terms  

 

 
DOI no: 10.1016/j.jmb.2003.10.033 J Mol Biol 334:853-861 (2003)
PubMed id: 14643652  
 
 
Crystal structure of the human liver X receptor beta ligand-binding domain in complex with a synthetic agonist.
S.Hoerer, A.Schmid, A.Heckel, R.M.Budzinski, H.Nar.
 
  ABSTRACT  
 
LXRbeta belongs to the nuclear hormone receptor superfamily of ligand-activated transcription factors. Its natural ligands are supposed to be oxidised derivatives of cholesterol. Stimulation of LXRbeta by agonists activates a number of genes that are involved in the regulation of lipid metabolism and cholesterol efflux from cells. Therefore, LXRbeta may represent a novel therapeutic target for the treatment of dyslipidemia and atherosclerosis.Here, we report the X-ray crystal structure of the LXRbeta ligand-binding domain in complex with a synthetic agonist, T-0901317. This compound occupies the ligand-binding pocket of the receptor, forms numerous lipophilic contacts with the protein and one crucial hydrogen bond to His435 and stabilises the agonist conformation of the receptor ligand-binding domain. The recruitment of the AF2-region of the protein is not achieved via direct polar interactions of the ligand with protein side-chains of this helical segment, but rather via few hydrophobic contacts and probably more importantly via indirect effects involving the pre-orientation of side-chains that surround the ligand-binding pocket and form the interface to the AF2-helix.On the basis of these results we propose a binding mode and a mechanism of action for the putative natural ligands, oxidised derivatives of cholesterol.
 
  Selected figure(s)  
 
Figure 4.
Figure 4. Stereo representation of the LXRb ligand-binding pocket with the proposed binding mode of 25-hydroxyl cholesterol. Carbon atoms of 25-hydroxyl cholesterol are coloured in orange. This Figure was prepared with MOLSCRIPT[37.] and Raster3D. [38.]
Figure 5.
Figure 5. Surface representation of the LXRb LBD with H12 removed. The fragment of T-0901317 facing H12 residues is shown at the center. Atoms at the interface with H12 are colored in orange (residues within 4.5 Å distance). The three residues in H12 directly contacting the ligand (Leu449, Leu453 and Trp457) are shown in stick representation.
 
  The above figures are reprinted by permission from Elsevier: J Mol Biol (2003, 334, 853-861) copyright 2003.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20655343 I.G.Schulman (2010).
Nuclear receptors as drug targets for metabolic disease.
  Adv Drug Deliv Rev, 62, 1307-1315.  
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.  
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.  
  19696872 K.M.Honório, L.B.Salum, R.C.Garratt, I.Polikarpov, and A.D.Andricopulo (2008).
Two- and three-dimensional quantitative structure-activity relationships studies on a series of liver x receptor ligands.
  Open Med Chem J, 2, 87-96.  
18651760 M.D.Krasowski, E.J.Reschly, and S.Ekins (2008).
Intrinsic disorder in nuclear hormone receptors.
  J Proteome Res, 7, 4359-4372.  
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.  
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
16354658 M.Albers, B.Blume, T.Schlueter, M.B.Wright, I.Kober, C.Kremoser, U.Deuschle, and M.Koegl (2006).
A novel principle for partial agonism of liver X receptor ligands. Competitive recruitment of activators and repressors.
  J Biol Chem, 281, 4920-4930.  
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
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.