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PDBsum entry 1u3r

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protein ligands Protein-protein interface(s) links
Transcription PDB id
1u3r
Jmol
Contents
Protein chains
231 a.a. *
Ligands
LYS-LEU-VAL-GLN-
LEU-LEU-THR-THR-
THR
×2
338 ×2
Waters ×131
* Residue conservation analysis
PDB id:
1u3r
Name: Transcription
Title: Crystal structure of estrogen receptor beta complexed with way-338
Structure: Estrogen receptor beta. Chain: a, b. Synonym: er-beta. Engineered: yes. Steroid receptor coactivator-1. Chain: c, d. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: esr2, nr3a2, estrb. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Synthetic: yes. Other_details: this sequence of this peptide can be found naturally in homo sapiens (human).
Biol. unit: Tetramer (from PQS)
Resolution:
2.21Å     R-factor:   0.218     R-free:   0.267
Authors: M.S.Malamas,E.S.Manas,R.E.Mcdevitt,I.Gunawan,Z.B.Xu, M.D.Collini,C.P.Miller,T.Dinh,R.A.Henderson,J.C.Keith Jr., H.A.Harris
Key ref: M.S.Malamas et al. (2004). Design and synthesis of aryl diphenolic azoles as potent and selective estrogen receptor-beta ligands. J Med Chem, 47, 5021-5040. PubMed id: 15456246 DOI: 10.1021/jm049719y
Date:
22-Jul-04     Release date:   26-Jul-05    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
Q92731  (ESR2_HUMAN) -  Estrogen receptor beta
Seq:
Struc:
 
Seq:
Struc:
530 a.a.
231 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: 10.1021/jm049719y J Med Chem 47:5021-5040 (2004)
PubMed id: 15456246  
 
 
Design and synthesis of aryl diphenolic azoles as potent and selective estrogen receptor-beta ligands.
M.S.Malamas, E.S.Manas, R.E.McDevitt, I.Gunawan, Z.B.Xu, M.D.Collini, C.P.Miller, T.Dinh, R.A.Henderson, J.C.Keith, H.A.Harris.
 
  ABSTRACT  
 
New diphenolic azoles as highly selective estrogen receptor-beta agonists are reported. The more potent and selective analogues of these series have comparable binding affinities for ERbeta as the natural ligand 17beta-estradiol but are >100-fold selective over ERalpha. Our design strategy not only followed a traditional SAR approach but also was supported by X-ray structures of ERbeta cocrystallized with various ligands as well as molecular modeling studies. These strategies enabled us to take advantage of a single conservative residue substitution in the ligand-binding pocket, ERalpha Met(421) --> ERbeta Ile(373), to optimize ERbeta selectivity. The 7-position-substituted benzoxazoles (Table 5) were the most selective ligands of both azole series, with ERB-041 (117) being >200-fold selective for ERbeta. The majority of ERbeta selective agonists tested that were at least approximately 50-fold selective displayed a consistent in vivo profile: they were inactive in several models of classic estrogen action (uterotrophic, osteopenia, and vasomotor instability models) and yet were active in the HLA-B27 transgenic rat model of inflammatory bowel disease. These data suggest that ERbeta-selective agonists are devoid of classic estrogenic effects and may offer a novel therapy to treat certain inflammatory conditions.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
19967775 F.Minutolo, M.Macchia, B.S.Katzenellenbogen, and J.A.Katzenellenbogen (2011).
Estrogen receptor β ligands: Recent advances and biomedical applications.
  Med Res Rev, 31, 364-442.  
21283915 K.Chanda, B.Maiti, G.S.Yellol, M.H.Chien, M.L.Kuo, and C.M.Sun (2011).
Polymer supported synthesis of novel benzoxazole linked benzimidazoles under microwave conditions: In vitro evaluation of VEGFR-3 kinase inhibition activity.
  Org Biomol Chem, 9, 1917-1926.  
21481497 S.Bertini, A.De Cupertinis, C.Granchi, B.Bargagli, T.Tuccinardi, A.Martinelli, M.Macchia, J.R.Gunther, K.E.Carlson, J.A.Katzenellenbogen, and F.Minutolo (2011).
Selective and potent agonists for estrogen receptor beta derived from molecular refinements of salicylaldoximes.
  Eur J Med Chem, 46, 2453-2462.  
20372741 C.Spiteri, C.Mason, F.Zhang, D.J.Ritson, P.Sharma, S.Keeling, and J.E.Moses (2010).
An efficient entry to 1,2-benzisoxazoles via 1,3-dipolar cycloaddition of in situ generated nitrile oxides and benzyne.
  Org Biomol Chem, 8, 2537-2542.  
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.  
19260733 D.Zhou, H.Zhou, C.C.Jenks, J.S.Lewis, J.A.Katzenellenbogen, and M.J.Welch (2009).
Bromination from the macroscopic level to the tracer radiochemical level: (76)Br radiolabeling of aromatic compounds via electrophilic substitution.
  Bioconjug Chem, 20, 808-816.  
19626711 S.Burendahl, C.Danciulescu, and L.Nilsson (2009).
Ligand unbinding from the estrogen receptor: a computational study of pathways and ligand specificity.
  Proteins, 77, 842-856.  
19609440 S.Paruthiyil, A.Cvoro, X.Zhao, Z.Wu, Y.Sui, R.E.Staub, S.Baggett, C.B.Herber, C.Griffin, M.Tagliaferri, H.A.Harris, I.Cohen, L.F.Bjeldanes, T.P.Speed, F.Schaufele, and D.C.Leitman (2009).
Drug and cell type-specific regulation of genes with different classes of estrogen receptor beta-selective agonists.
  PLoS One, 4, e6271.  
18004284 A.E.Clipperton, J.M.Spinato, C.Chernets, D.W.Pfaff, and E.Choleris (2008).
Differential effects of estrogen receptor alpha and beta specific agonists on social learning of food preferences in female mice.
  Neuropsychopharmacology, 33, 2362-2375.  
18312354 C.A.Green, M.B.Peter, V.Speirs, and A.M.Shaaban (2008).
The potential role of ER beta isoforms in the clinical management of breast cancer.
  Histopathology, 53, 374-380.  
17229415 I.M.Kapetanovic (2008).
Computer-aided drug discovery and development (CADDD): in silico-chemico-biological approach.
  Chem Biol Interact, 171, 165-176.  
18374292 R.Kennelly, D.O.Kavanagh, A.M.Hogan, and D.C.Winter (2008).
Oestrogen and the colon: potential mechanisms for cancer prevention.
  Lancet Oncol, 9, 385-391.  
17609799 H.Shimizu, and M.Murakami (2007).
Synthesis of alpha-keto esters by the rhodium-catalysed reaction of cyanoformate with arylboronic acids.
  Chem Commun (Camb), (), 2855-2857.  
17243946 M.Braddock (2007).
Advances in Anti-Inflammatory Therapeutics: 20-21 November 2006, London, UK.
  Expert Opin Investig Drugs, 16, 257-261.  
16688783 A.M.Davis, M.R.Ellersieck, K.M.Grimm, and C.S.Rosenfeld (2006).
The effects of the selective estrogen receptor modulators, methyl-piperidino-pyrazole (MPP), and raloxifene in normal and cancerous endometrial cell lines and in the murine uterus.
  Mol Reprod Dev, 73, 1034-1044.  
16939388 A.Mihalyi, P.Simsa, K.C.Mutinda, C.Meuleman, J.M.Mwenda, and T.M.D'Hooghe (2006).
Emerging drugs in endometriosis.
  Expert Opin Emerg Drugs, 11, 503-524.  
17001712 L.Toschi, J.Hilbig, T.Wintermantel, A.Engelhaupt, A.Walter, K.H.Fritzemeier, and A.Hillisch (2006).
Protein-structure-based prediction of animal model suitability for pharmacodynamic studies of subtype-selective estrogens.
  ChemMedChem, 1, 1237-1248.  
16914190 P.Ascenzi, A.Bocedi, and M.Marino (2006).
Structure-function relationship of estrogen receptor alpha and beta: impact on human health.
  Mol Aspects Med, 27, 299-402.  
16648639 R.W.Hsieh, S.S.Rajan, S.K.Sharma, Y.Guo, E.R.DeSombre, M.Mrksich, and G.L.Greene (2006).
Identification of ligands with bicyclic scaffolds provides insights into mechanisms of estrogen receptor subtype selectivity.
  J Biol Chem, 281, 17909-17919.
PDB codes: 1zky 2b1v 2fai
15550624 K.M.Egan, J.A.Lawson, S.Fries, B.Koller, D.J.Rader, E.M.Smyth, and G.A.Fitzgerald (2004).
COX-2-derived prostacyclin confers atheroprotection on female mice.
  Science, 306, 1954-1957.  
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 codes are shown on the right.