PDBsum entry 1uom

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Nuclear protein PDB id
Jmol PyMol
Protein chain
232 a.a. *
Waters ×89
* Residue conservation analysis
PDB id:
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)
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
11-Apr-03     Release date:   03-Jul-03    
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Protein chain
Pfam   ArchSchema ?
P03372  (ESR1_HUMAN) -  Estrogen receptor
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.
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.  
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