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PDBsum entry 1rdt

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Hormone/growth factor PDB id
1rdt
Jmol
Contents
Protein chains
211 a.a. *
253 a.a. *
Ligands
HIS-LYS-ILE-LEU-
HIS-ARG-LEU-LEU-
GLN
LYS-GLN-LEU-SER-
GLU-LEU-LEU
L79
570
Waters ×205
* Residue conservation analysis
PDB id:
1rdt
Name: Hormone/growth factor
Title: Crystal structure of a new rexinoid bound to the rxralpha ligand binding doamin in the rxralpha/ppargamma heterodimer
Structure: Retinoic acid receptor rxr-alpha. Chain: a. Fragment: ligand binding doamin. Synonym: rxralpha. Engineered: yes. Lxxll motif coactivator. Chain: b. Fragment: lxxll peptide. Engineered: yes.
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: rxra, nr2b1. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Synthetic: yes. Gene: pparg, nr1c3. Synthetic: yes
Biol. unit: Tetramer (from PQS)
Resolution:
2.40Å     R-factor:   0.221     R-free:   0.259
Authors: C.D.Haffner,J.M.Lenhard,A.B.Miller,D.L.Mcdougald,K.Dwornik, O.R.Ittoop,R.T.Gampe Jr.,H.E.Xu,S.Blanchard,V.G.Montana
Key ref: C.D.Haffner et al. (2004). Structure-based design of potent retinoid X receptor alpha agonists. J Med Chem, 47, 2010-2029. PubMed id: 15056000 DOI: 10.1021/jm030565g
Date:
06-Nov-03     Release date:   09-Nov-04    
PROCHECK
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 Headers
 References

Protein chain
Pfam   ArchSchema ?
P19793  (RXRA_HUMAN) -  Retinoic acid receptor RXR-alpha
Seq:
Struc:
462 a.a.
211 a.a.
Protein chain
Pfam   ArchSchema ?
P37231  (PPARG_HUMAN) -  Peroxisome proliferator-activated receptor gamma
Seq:
Struc:
505 a.a.
253 a.a.*
Key:    PfamA 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     5 terms  

 

 
DOI no: 10.1021/jm030565g J Med Chem 47:2010-2029 (2004)
PubMed id: 15056000  
 
 
Structure-based design of potent retinoid X receptor alpha agonists.
C.D.Haffner, J.M.Lenhard, A.B.Miller, D.L.McDougald, K.Dwornik, O.R.Ittoop, R.T.Gampe, H.E.Xu, S.Blanchard, V.G.Montana, T.G.Consler, R.K.Bledsoe, A.Ayscue, D.Croom.
 
  ABSTRACT  
 
A series of tetrahydrobenzofuranyl and tetrahydrobenzothienyl propenoic acids that showed potent agonist activity against RXRalpha were synthesized via a structure-based design approach. Among the compounds studied, 46a,b showed not only very good potency against RXRalpha (K(i) = 6 nM) but was also found to be greater than 167-fold selective vs RARalpha (K(i) > 1000 nM). This compound profiled out as a full agonist in a cell-based transient transfection assay (EC(50) = 3 nM). The two antipodes were separated via chiral chromatography, and 46b was found to be 40-fold more potent than 46a. Interestingly, cocrystallization of 46a,b with the RXRalpha protein generated a liganded structure whereby the (S)-antipode was found in the binding pocket. Given orally in db/db mice or ZDF rats, 46a,b showed a significant glucose-lowering effect and an increase in liver mass. Triglycerides decreased significantly in db/db mice but increased in the ZDF rats. A dose-dependent decrease of nonesterified free fatty acids was seen in ZDF rats but not in db/db mice. These differences indicate a species specific effect of RXR agonists on lipid metabolism.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
  21560232 R.P.Khandare, K.R.Vaze, and S.V.Bhat (2011).
Synthesis and antitumor activity of new retinobenzoic acids.
  Chem Biodivers, 8, 841-849.  
19746174 S.N.Lewis, J.Bassaganya-Riera, and D.R.Bevan (2010).
Virtual Screening as a Technique for PPAR Modulator Discovery.
  PPAR Res, 2010, 861238.  
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.  
19378296 M.I.Dawson, M.Ye, X.Cao, L.Farhana, Q.Y.Hu, Y.Zhao, L.P.Xu, A.Kiselyuk, R.G.Correa, L.Yang, T.Hou, J.C.Reed, P.Itkin-Ansari, F.Levine, M.F.Sanner, J.A.Fontana, and X.K.Zhang (2009).
Derivation of a retinoid X receptor scaffold from peroxisome proliferator-activated receptor gamma ligand 1-Di(1H-indol-3-yl)methyl-4-trifluoromethylbenzene.
  ChemMedChem, 4, 1106-1119.  
19919089 S.Das, A.Kokardekar, and C.M.Breneman (2009).
Rapid comparison of protein binding site surfaces with property encoded shape distributions.
  J Chem Inf Model, 49, 2863-2872.  
18375192 W.A.Alaynick (2008).
Nuclear receptors, mitochondria and lipid metabolism.
  Mitochondrion, 8, 329-337.  
17462987 A.L.Ambrosio, S.M.Dias, I.Polikarpov, R.B.Zurier, S.H.Burstein, and R.C.Garratt (2007).
Ajulemic acid, a synthetic nonpsychoactive cannabinoid acid, bound to the ligand binding domain of the human peroxisome proliferator-activated receptor gamma.
  J Biol Chem, 282, 18625-18633.
PDB code: 2om9
17446857 K.T.Liby, M.M.Yore, and M.B.Sporn (2007).
Triterpenoids and rexinoids as multifunctional agents for the prevention and treatment of cancer.
  Nat Rev Cancer, 7, 357-369.  
17906642 L.Altucci, M.D.Leibowitz, K.M.Ogilvie, A.R.de Lera, and H.Gronemeyer (2007).
RAR and RXR modulation in cancer and metabolic disease.
  Nat Rev Drug Discov, 6, 793-810.  
17905826 X.Yan, E.Pérez, M.Leid, M.I.Schimerlik, A.R.de Lera, and M.L.Deinzer (2007).
Deuterium exchange and mass spectrometry reveal the interaction differences of two synthetic modulators of RXRalpha LBD.
  Protein Sci, 16, 2491-2501.  
17076708 T.Sakuta, and T.Kanayama (2006).
Marked improvement induced in photoaged skin of hairless mouse by ER36009, a novel RARgamma-specific retinoid, but not by ER35794, an RXR-selective agonist.
  Int J Dermatol, 45, 1288-1295.  
16006182 S.P.Williams, L.F.Kuyper, and K.H.Pearce (2005).
Recent applications of protein crystallography and structure-guided drug design.
  Curr Opin Chem Biol, 9, 371-380.  
16179348 X.Li, P.A.Hansen, L.Xi, R.A.Chandraratna, and C.F.Burant (2005).
Distinct mechanisms of glucose lowering by specific agonists for peroxisomal proliferator activated receptor gamma and retinoic acid X receptors.
  J Biol Chem, 280, 38317-38327.  
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.