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PDBsum entry 1yye

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protein ligands Protein-protein interface(s) links
Transcription PDB id
1yye
Jmol
Contents
Protein chains
228 a.a. *
Ligands
HIS-LYS-LEU-VAL-
GLN-LEU-LEU-THR-
THR-THR
×2
196 ×2
Waters ×299
* Residue conservation analysis
PDB id:
1yye
Name: Transcription
Title: Crystal structure of estrogen receptor beta complexed with way-202196
Structure: Estrogen receptor beta. Chain: a, b. Fragment: ligand binding domain. Synonym: er-beta. Engineered: yes. Steroid receptor coactivator-1. Chain: c, d. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: esr2, estrb, nr3a2. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Synthetic: yes. Other_details: this sequence was derived from steroid receptor coactivator-1
Biol. unit: Tetramer (from PQS)
Resolution:
2.03Å     R-factor:   0.223     R-free:   0.269
Authors: R.E.Mewshaw,R.J.Edsall Jr.,C.Yang,E.S.Manas,Z.B.Xu, R.A.Henderson,J.C.Keith Jr.,H.A.Harris
Key ref: R.E.Mewshaw et al. (2005). ERbeta ligands. 3. Exploiting two binding orientations of the 2-phenylnaphthalene scaffold to achieve ERbeta selectivity. J Med Chem, 48, 3953-3979. PubMed id: 15943471 DOI: 10.1021/jm058173s
Date:
24-Feb-05     Release date:   28-Feb-06    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
Q92731  (ESR2_HUMAN) -  Estrogen receptor beta
Seq:
Struc:
 
Seq:
Struc:
530 a.a.
228 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     3 terms  

 

 
DOI no: 10.1021/jm058173s J Med Chem 48:3953-3979 (2005)
PubMed id: 15943471  
 
 
ERbeta ligands. 3. Exploiting two binding orientations of the 2-phenylnaphthalene scaffold to achieve ERbeta selectivity.
R.E.Mewshaw, R.J.Edsall, C.Yang, E.S.Manas, Z.B.Xu, R.A.Henderson, J.C.Keith, H.A.Harris.
 
  ABSTRACT  
 
The 2-phenylnaphthalene scaffold was explored as a simplified version of genistein in order to identify ER selective ligands. With the aid of docking studies, positions 1, 4, and 8 of the 2-phenylnaphthalene template were predicted to be the most potentially influential positions to enhance ER selectivity using two different binding orientations. Both orientations have the phenol moiety mimicking the A-ring of genistein. Several compounds predicted to adopt orientations similar to that of genistein when bound to ERbeta were observed to have slightly higher ER affinity and selectivity than genistein. The second orientation we exploited, which was different from that of genistein when bound to ERbeta, resulted in the discovery of several compounds that had superior ER selectivity and affinity versus genistein. X-ray structures of two ER selective compounds (i.e., 15 and 47) confirmed the alternate binding mode and suggested that substituents at positions 1 and 8 were responsible for inducing selectivity. One compound (i.e., 47, WAY-202196) was further examined and found to be effective in two models of inflammation, suggesting that targeting ER may be therapeutically useful in treating certain chronic inflammatory diseases.
 

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.  
20957105 Z.Wang, Y.Li, C.Ai, and Y.Wang (2010).
In silico prediction of estrogen receptor subtype binding affinity and selectivity using statistical methods and molecular docking with 2-arylnaphthalenes and 2-arylquinolines.
  Int J Mol Sci, 11, 3434-3458.  
19368882 D.L.Mobley, and K.A.Dill (2009).
Binding of small-molecule ligands to proteins: "what you see" is not always "what you get".
  Structure, 17, 489-498.  
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.  
16862218 H.A.Harris (2006).
The unexpected science of estrogen receptor-beta selective agonists: a new class of anti-inflammatory agents?
  Nucl Recept Signal, 4, e012.  
16755255 P.A.Cristofaro, S.M.Opal, J.E.Palardy, N.A.Parejo, J.Jhung, J.C.Keith, and H.A.Harris (2006).
WAY-202196, a selective estrogen receptor-beta agonist, protects against death in experimental septic shock.
  Crit Care Med, 34, 2188-2193.  
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
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