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PDBsum entry 1uom

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Nuclear protein PDB id
1uom
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Contents
Protein chain
232 a.a. *
Ligands
PTI
Waters ×89
* Residue conservation analysis
PDB id:
1uom
Name: Nuclear protein
Title: The structure of estrogen receptor in complex with a selective and potent tetrahydroisochiolin ligand.
Structure: Estrogen receptor. Chain: a. Fragment: ligand binding domain, residues 301 - 553. Synonym: estrogen receptor alpha, er, estradiol receptor, er-alpha, esr1, nr3a1, esr. Engineered: yes. Mutation: yes. Other_details: nvp-add562 l solvent s
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 469008.
Biol. unit: Dimer (from PDB file)
Resolution:
2.28Å     R-factor:   0.235     R-free:   0.287
Authors: W.Stark,S.F.Bischoff,T.Buhl,B.Fournier,C.Halleux,J.Kallen, H.Keller,J.Renaud
Key ref: J.Renaud et al. (2003). Estrogen receptor modulators: identification and structure-activity relationships of potent ERalpha-selective tetrahydroisoquinoline ligands. J Med Chem, 46, 2945-2957. PubMed id: 12825935 DOI: 10.1021/jm030086h
Date:
11-Apr-03     Release date:   03-Jul-03    
PROCHECK
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 Headers
 References

Protein chain
Pfam   ArchSchema ?
P03372  (ESR1_HUMAN) -  Estrogen receptor
Seq:
Struc:
 
Seq:
Struc:
595 a.a.
232 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 2 residue positions (black crosses)

 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     2 terms  

 

 
DOI no: 10.1021/jm030086h J Med Chem 46:2945-2957 (2003)
PubMed id: 12825935  
 
 
Estrogen receptor modulators: identification and structure-activity relationships of potent ERalpha-selective tetrahydroisoquinoline ligands.
J.Renaud, S.F.Bischoff, T.Buhl, P.Floersheim, B.Fournier, C.Halleux, J.Kallen, H.Keller, J.M.Schlaeppi, W.Stark.
 
  ABSTRACT  
 
As part of a program aimed at the development of selective estrogen receptor modulators (SERMs), tetrahydroisoquinoline derivative 27 was discovered by high throughput screening. Successive replacements of the p-F substituent of 27 by an aminoethoxy side chain and of the 1-H of the tetrahydroisoquinoline core by a 1-Me group provided analogues 19 and 20. These compounds showed potencies in a cell-based reporter gene assay (ERE assay) varying between 0.6 and 20 nM and displayed antagonist behaviors in the MCF-7 human breast adenocarcinoma cell line with IC(50)s in the range of 2-36 nM. The effect of N-phenyl substituents on the activity and pharmacokinetic properties of tetrahydroisoquinoline analogues was explored. As a result of this investigation, two potent derivatives bearing a p-F N-aryl group, 19c and 20c, were discovered as candidates suitable for further profiling. To gain insight into the ligand-receptor interaction, the X-ray crystallographic structure of the 1-H tetrahydroisoquinoline derivative (R)-18a in complex with ERalpha-ligand binding domain (LBD)(301)(-)(553)/C-->S triple mutant was solved to 2.28 A. An overlay of this X-ray crystal structure with that reported for the complex of ERalpha-LBD(301)(-)(553)/carboxymethylated C and raloxifene (5) shows that both compounds bind to the same cleft of the receptor and display comparable binding modes, with differences being observed in the conformation of their "D-ring" phenyl groups.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
18068350 V.C.Jordan (2008).
Tamoxifen: catalyst for the change to targeted therapy.
  Eur J Cancer, 44, 30-38.  
  18097104 V.Cura, M.Gangloff, S.Eiler, D.Moras, and M.Ruff (2008).
Cleaved thioredoxin fusion protein enables the crystallization of poorly soluble ERalpha in complex with synthetic ligands.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 64, 54-57.  
17456742 F.F.Vajdos, L.R.Hoth, K.F.Geoghegan, S.P.Simons, P.K.LeMotte, D.E.Danley, M.J.Ammirati, and J.Pandit (2007).
The 2.0 A crystal structure of the ERalpha ligand-binding domain complexed with lasofoxifene.
  Protein Sci, 16, 897-905.
PDB code: 2ouz
16319980 D.T.Trafalis, G.D.Geromichalos, C.Koukoulitsa, A.Papageorgiou, P.Karamanakos, and C.Camoutsis (2006).
Lactandrate: a D-homo-aza-androsterone alkylator in the treatment of breast cancer.
  Breast Cancer Res Treat, 97, 17-31.  
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.  
15726586 J.M.Yang, and T.W.Shen (2005).
A pharmacophore-based evolutionary approach for screening selective estrogen receptor modulators.
  Proteins, 59, 205-220.  
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.

 

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