PDBsum entry 1x7e

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protein ligands Protein-protein interface(s) links
Transcription PDB id
Protein chains
238 a.a. *
11 a.a. *
244 ×2
Waters ×72
* Residue conservation analysis
PDB id:
Name: Transcription
Title: Crystal structure of estrogen receptor alpha complexed with way-244
Structure: Estrogen receptor 1 (alpha). Chain: a, b. Synonym: er, estradiol receptor, er-alpha. Engineered: yes. Steroid receptor coactivator-3. Chain: c, d. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: esr1, nr3a1, esr. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Synthetic: yes. Other_details: this sequence was derived from steroid receptor coactivator-3
Biol. unit: Dimer (from PQS)
2.80Å     R-factor:   0.219     R-free:   0.286
Authors: E.S.Manas,R.J.Unwalla,Z.B.Xu,M.S.Malamas,C.P.Miller, H.A.Harris,C.Hsiao,T.Akopian,W.T.Hum,K.Malakian,S.Wolfrom, A.Bapat,R.A.Bhat,M.L.Stahl,W.S.Somers,J.C.Alvarez
Key ref: E.S.Manas et al. (2004). Structure-based design of estrogen receptor-beta selective ligands. J Am Chem Soc, 126, 15106-15119. PubMed id: 15548008 DOI: 10.1021/ja047633o
13-Aug-04     Release date:   01-Mar-05    
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Protein chains
Pfam   ArchSchema ?
P03372  (ESR1_HUMAN) -  Estrogen receptor
595 a.a.
238 a.a.*
Protein chains
No UniProt id for this chain
Struc: 11 a.a.
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 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/ja047633o J Am Chem Soc 126:15106-15119 (2004)
PubMed id: 15548008  
Structure-based design of estrogen receptor-beta selective ligands.
E.S.Manas, R.J.Unwalla, Z.B.Xu, M.S.Malamas, C.P.Miller, H.A.Harris, C.Hsiao, T.Akopian, W.T.Hum, K.Malakian, S.Wolfrom, A.Bapat, R.A.Bhat, M.L.Stahl, W.S.Somers, J.C.Alvarez.
We present the structure-based optimization of a series of estrogen receptor-beta (ERbeta) selective ligands. X-ray cocrystal structures of these ligands complexed to both ERalpha and ERbeta are described. We also discuss how molecular modeling was used to take advantage of subtle differences between the two binding cavities in order to optimize selectivity for ERbeta over ERalpha. Quantum chemical calculations are utilized to gain insight into the mechanism of selectivity enhancement. Despite only two relatively conservative residue substitutions in the ligand binding pocket, the most selective compounds have greater than 100-fold selectivity for ERbeta relative to ERalpha when measured using a competitive radioligand binding assay.

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.  
21038436 Y.Mu, S.Peng, A.Zhang, and L.Wang (2011).
Role of pocket flexibility in the modulation of estrogen receptor alpha by key residue arginine 394.
  Environ Toxicol Chem, 30, 330-336.  
  20427257 A.Matsushima, X.Liu, H.Okada, M.Shimohigashi, and Y.Shimohigashi (2010).
Bisphenol AF is a full agonist for the estrogen receptor ERalpha but a highly specific antagonist for ERbeta.
  Environ Health Perspect, 118, 1267-1272.  
20345171 C.Bissantz, B.Kuhn, and M.Stahl (2010).
A medicinal chemist's guide to molecular interactions.
  J Med Chem, 53, 5061-5084.  
20708050 E.K.Shanle, and W.Xu (2010).
Selectively targeting estrogen receptors for cancer treatment.
  Adv Drug Deliv Rev, 62, 1265-1276.  
20668547 L.Zhang, B.E.Blackman, M.D.Schonemann, T.Zogovic-Kapsalis, X.Pan, M.Tagliaferri, H.A.Harris, I.Cohen, R.A.Pera, S.H.Mellon, R.I.Weiner, and D.C.Leitman (2010).
Estrogen receptor beta-selective agonists stimulate calcium oscillations in human and mouse embryonic stem cell-derived neurons.
  PLoS One, 5, e11791.  
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.  
20922740 S.Möcklinghoff, R.Rose, M.Carraz, A.Visser, C.Ottmann, and L.Brunsveld (2010).
Synthesis and crystal structure of a phosphorylated estrogen receptor ligand binding domain.
  Chembiochem, 11, 2251-2254.
PDB codes: 3oll 3ols
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.  
18989626 H.Shadnia, J.S.Wright, and J.M.Anderson (2009).
Interaction force diagrams: new insight into ligand-receptor binding.
  J Comput Aided Mol Des, 23, 185-194.  
19626425 I.Hartman, A.R.Gillies, S.Arora, C.Andaya, N.Royapet, W.J.Welsh, D.W.Wood, and R.J.Zauhar (2009).
Application of screening methods, shape signatures and engineered biosensors in early drug discovery process.
  Pharm Res, 26, 2247-2258.  
19333551 S.Ellmann, H.Sticht, F.Thiel, M.W.Beckmann, R.Strick, and P.L.Strissel (2009).
Estrogen and progesterone receptors: from molecular structures to clinical targets.
  Cell Mol Life Sci, 66, 2405-2426.  
17090028 C.Ramesh, B.Bryant, T.Nayak, C.M.Revankar, T.Anderson, K.E.Carlson, J.A.Katzenellenbogen, L.A.Sklar, J.P.Norenberg, E.R.Prossnitz, and J.B.Arterburn (2006).
Linkage effects on binding affinity and activation of GPR30 and estrogen receptors ERalpha/beta with tridentate pyridin-2-yl hydrazine tricarbonyl-Re/(99m)Tc(I) chelates.
  J Am Chem Soc, 128, 14476-14477.  
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.  
16892386 J.T.Moore, J.L.Collins, and K.H.Pearce (2006).
The nuclear receptor superfamily and drug discovery.
  ChemMedChem, 1, 504-523.  
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
16978016 T.S.Dowers, Z.H.Qin, G.R.Thatcher, and J.L.Bolton (2006).
Bioactivation of Selective Estrogen Receptor Modulators (SERMs).
  Chem Res Toxicol, 19, 1125-1137.  
16006182 S.P.Williams, L.F.Kuyper, and K.H.Pearce (2005).
Recent applications of protein crystallography and structure-guided drug design.
  Curr Opin Chem Biol, 9, 371-380.  
15576033 E.S.Manas, Z.B.Xu, R.J.Unwalla, and W.S.Somers (2004).
Understanding the selectivity of genistein for human estrogen receptor-beta using X-ray crystallography and computational methods.
  Structure, 12, 2197-2207.
PDB codes: 1x7j 1x7r
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.