PDBsum entry 1r5k

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protein ligands Protein-protein interface(s) links
DNA binding protein PDB id
Protein chains
236 a.a. *
GW5 ×3
Waters ×39
* Residue conservation analysis
PDB id:
Name: DNA binding protein
Title: Human estrogen receptor alpha ligand-binding domain in compl gw5638
Structure: Estrogen receptor. Chain: a, b, c. Fragment: ligand-binding domain (residues 297-554). Synonym: er, estradiol receptor, er-alpha. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: esr1 or nr3a1 or esr. Expressed in: escherichia coli. Expression_system_taxid: 562.
Biol. unit: Dimer (from PDB file)
2.70Å     R-factor:   0.208     R-free:   0.236
Authors: Y.-L.Wu,X.Yang,Z.Ren,D.P.Mcdonnell,J.D.Norris,T.M.Willson,G.
Key ref:
Y.L.Wu et al. (2005). Structural basis for an unexpected mode of SERM-mediated ER antagonism. Mol Cell, 18, 413-424. PubMed id: 15893725 DOI: 10.1016/j.molcel.2005.04.014
10-Oct-03     Release date:   23-Nov-04    
Go to PROCHECK summary

Protein chains
Pfam   ArchSchema ?
P03372  (ESR1_HUMAN) -  Estrogen receptor
595 a.a.
236 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: 10.1016/j.molcel.2005.04.014 Mol Cell 18:413-424 (2005)
PubMed id: 15893725  
Structural basis for an unexpected mode of SERM-mediated ER antagonism.
Y.L.Wu, X.Yang, Z.Ren, D.P.McDonnell, J.D.Norris, T.M.Willson, G.L.Greene.
Tamoxifen is effective for the prevention and treatment of estrogen-dependent breast cancers, but is associated with an increased incidence of endometrial tumors. We report the crystal structure of the estrogen receptor alpha (ERalpha) ligand binding domain (LBD) bound to the structurally similar compound GW5638, which has therapeutic potential and does not stimulate the uterus. Like tamoxifen, GW5638 relocates the carboxy-terminal helix (H12) to the known coactivator-docking site in the ERalpha LBD. However, GW5638 repositions residues in H12 through specific contacts with the N terminus of this helix. In contrast to tamoxifen, the resulting increase in exposed hydrophobic surface of ERalpha LBD correlates with a significant destabilization of ERalpha in MCF-7 cells. Thus, the GW5638-ERalpha LBD structure reveals an unexpected mode of SERM-mediated ER antagonism, in which the stability of ERalpha is decreased through an altered position of H12. This dual mechanism of antagonism may explain why GW5638 can inhibit tamoxifen-resistant breast tumors.
  Selected figure(s)  
Figure 2.
Figure 2. Ligand-LBD Interactions in GW5638-ERα LBD and OHT-ERα LBD
Figure 3.
Figure 3. Superimposed Structures of GW5638-ERα LBD and OHT-ERα LBD
  The above figures are reprinted by permission from Cell Press: Mol Cell (2005, 18, 413-424) copyright 2005.  
  Figures were selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21243720 D.Cheng, and M.T.Bedford (2011).
Xenoestrogens regulate the activity of arginine methyltransferases.
  Chembiochem, 12, 323-329.  
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.  
20708050 E.K.Shanle, and W.Xu (2010).
Selectively targeting estrogen receptors for cancer treatment.
  Adv Drug Deliv Rev, 62, 1265-1276.  
20334372 K.J.Kieser, D.W.Kim, K.E.Carlson, B.S.Katzenellenbogen, and J.A.Katzenellenbogen (2010).
Characterization of the pharmacophore properties of novel selective estrogen receptor downregulators (SERDs).
  J Med Chem, 53, 3320-3329.  
20723571 L.Jin, and Y.Li (2010).
Structural and functional insights into nuclear receptor signaling.
  Adv Drug Deliv Rev, 62, 1218-1226.  
19526339 M.Nichols, P.Cheng, Y.Liu, B.Kanterewicz, P.A.Hershberger, and K.S.McCarty (2010).
Breast cancer-derived M543V mutation in helix 12 of estrogen receptor alpha inverts response to estrogen and SERMs.
  Breast Cancer Res Treat, 120, 761-768.  
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.  
19063592 A.Amadasi, A.Mozzarelli, C.Meda, A.Maggi, and P.Cozzini (2009).
Identification of xenoestrogens in food additives by an integrated in silico and in vitro approach.
  Chem Res Toxicol, 22, 52-63.  
19389631 J.D.Norris, J.D.Joseph, A.B.Sherk, D.Juzumiene, P.S.Turnbull, S.W.Rafferty, H.Cui, E.Anderson, D.Fan, D.A.Dye, X.Deng, D.Kazmin, C.Y.Chang, T.M.Willson, and D.P.McDonnell (2009).
Differential presentation of protein interaction surfaces on the androgen receptor defines the pharmacological actions of bound ligands.
  Chem Biol, 16, 452-460.  
  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.  
17654759 C.R.Overk, K.W.Peng, R.T.Asghodom, I.Kastrati, D.D.Lantvit, Z.Qin, J.Frasor, J.L.Bolton, and G.R.Thatcher (2007).
Structure-activity relationships for a family of benzothiophene selective estrogen receptor modulators including raloxifene and arzoxifene.
  ChemMedChem, 2, 1520-1526.  
17387660 M.Awais, M.Sato, and Y.Umezawa (2007).
Imaging of selective nuclear receptor modulator-induced conformational changes in the nuclear receptor to allow interaction with coactivator and corepressor proteins in living cells.
  Chembiochem, 8, 737-743.  
17033922 M.Fan, E.L.Rickert, L.Chen, S.A.Aftab, K.P.Nephew, and R.V.Weatherman (2007).
Characterization of molecular and structural determinants of selective estrogen receptor downregulators.
  Breast Cancer Res Treat, 103, 37-44.  
17300979 V.Nahoum, and W.Bourguet (2007).
Androgen and estrogen receptors: potential of crystallography in the fight against cancer.
  Int J Biochem Cell Biol, 39, 1280-1287.  
17339601 W.Gao, and J.T.Dalton (2007).
Ockham's razor and selective androgen receptor modulators (SARMs): are we overlooking the role of 5alpha-reductase?
  Mol Interv, 7, 10-13.  
17072333 K.De Bosscher, W.Vanden Berghe, and G.Haegeman (2006).
Cross-talk between nuclear receptors and nuclear factor kappaB.
  Oncogene, 25, 6868-6886.  
16618973 M.Kishimoto, R.Fujiki, S.Takezawa, Y.Sasaki, T.Nakamura, K.Yamaoka, H.Kitagawa, and S.Kato (2006).
Nuclear receptor mediated gene regulation through chromatin remodeling and histone modifications.
  Endocr J, 53, 157-172.  
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.  
16459337 X.Long, and K.P.Nephew (2006).
Fulvestrant (ICI 182,780)-dependent interacting proteins mediate immobilization and degradation of estrogen receptor-alpha.
  J Biol Chem, 281, 9607-9615.  
16324147 S.Ogawa, H.Oishi, Y.Mezaki, M.Kouzu-Fujita, R.Matsuyama, M.Nakagomi, E.Mori, E.Murayama, H.Nagasawa, H.Kitagawa, J.Yanagisawa, T.Yano, and S.Kato (2005).
Repressive domain of unliganded human estrogen receptor alpha associates with Hsc70.
  Genes Cells, 10, 1095-1102.  
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.