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PDBsum entry 2zy0

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protein ligands Protein-protein interface(s) links
Transcription PDB id
2zy0
Jmol
Contents
Protein chains
215 a.a. *
11 a.a. *
Ligands
HIS-LYS-ILE-LEU-
HIS-ARG-LEU-LEU-
GLN-ASP
21P ×2
Waters ×26
* Residue conservation analysis
PDB id:
2zy0
Name: Transcription
Title: Crystal structure of the human rxr alpha ligand binding domain bound to a synthetic agonist compound and a coactivator peptide
Structure: Retinoic acid receptor rxr-alpha. Chain: a, c. Fragment: ligand binding domain. Synonym: retinoid x receptor alpha, nuclear receptor subfamily 2 group b member 1. Engineered: yes. Grip1 from nuclear receptor coactivator 2. Chain: b, d. Synonym: ncoa-2, transcriptional intermediary factor 2,
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Synthetic: yes. Other_details: this sequence occurs naturally in humans.
Resolution:
2.90Å     R-factor:   0.221     R-free:   0.289
Authors: Y.Sato,P.Antony,N.Rochel,D.Moras,Structural Genomics Consortium For Research On Gene Expression (Sgcges)
Key ref: W.P.Lippert et al. (2009). Silicon analogues of the RXR-selective retinoid agonist SR11237 (BMS649): chemistry and biology. ChemMedChem, 4, 1143-1152. PubMed id: 19496083
Date:
09-Jan-09     Release date:   11-Aug-09    
PROCHECK
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 Headers
 References

Protein chains
Pfam   ArchSchema ?
P19793  (RXRA_HUMAN) -  Retinoic acid receptor RXR-alpha
Seq:
Struc:
462 a.a.
215 a.a.
Protein chain
Pfam   ArchSchema ?
Q15596  (NCOA2_HUMAN) -  Nuclear receptor coactivator 2
Seq:
Struc:
 
Seq:
Struc:
 
Seq:
Struc:
1464 a.a.
11 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  

 

 
ChemMedChem 4:1143-1152 (2009)
PubMed id: 19496083  
 
 
Silicon analogues of the RXR-selective retinoid agonist SR11237 (BMS649): chemistry and biology.
W.P.Lippert, C.Burschka, K.Götz, M.Kaupp, D.Ivanova, C.Gaudon, Y.Sato, P.Antony, N.Rochel, D.Moras, H.Gronemeyer, R.Tacke.
 
  ABSTRACT  
 
C/Si switch: Twofold sila-substitution (C/Si exchange) in the RXR-selective retinoids 4 a (SR11237) and 5 a leads to 4 b (disila-SR11237) and 5 b, respectively. Chemistry and biology of the C/Si pairs are reported.SR11237 (BMS649, 4 a) is a pan-RXR-selective retinoid agonist. Its silicon analogue, disila-SR11237 (4 b; twofold C/Si exchange), was prepared in a multistep synthesis by starting from 1,2-bis(ethynyldimethylsilyl)ethane. In addition, the related C/Si analogues 5 a and 5 b, with an indane (disila-indane) instead of a tetraline (disila-tetraline) skeleton, were synthesized. The C/Si pairs 4 a/4 b and 5 a/5 b were studied for their interaction with retinoid receptors and were demonstrated to be highly potent RXR-selective ("rexinoid") agonists. Interestingly, twofold C/Si exchange in the indane moiety of 5 a resulted in a 10-fold increase in biological activity of the corresponding silicon-containing rexinoid 5 b, possibly resulting from an increased receptor affinity or a divergent allosteric effect on co-regulator-binding surfaces. The crystal structures of the ternary complexes formed by 5 a and 5 b, respectively, with the ligand-binding domain of hRXRalpha and a peptide of the co-activator TIF2/GRIP1 revealed additional interactions of the disila analogue 5 b with the H7 and H11 residues, supporting the first option of increased binding affinity. This is the first demonstration of an increase in binding affinity of a ligand to a nuclear receptor by C/Si replacement, thereby adding this C/Si switch strategy to the repertoire of nuclear receptor ligand design.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
19790202 R.Tacke, V.Müller, M.W.Büttner, W.P.Lippert, R.Bertermann, J.O.Daiss, H.Khanwalkar, A.Furst, C.Gaudon, and H.Gronemeyer (2009).
Synthesis and pharmacological characterization of Disila-AM80 (Disila-tamibarotene) and Disila-AM580, silicon analogues of the RARalpha-selective retinoid agonists AM80 (Tamibarotene) and AM580.
  ChemMedChem, 4, 1797-1802.  
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