PDBsum entry 2q6j

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Transcription PDB id
Protein chains
242 a.a. *
A48 ×2
Waters ×1
* Residue conservation analysis
PDB id:
Name: Transcription
Title: Crystal structure of estrogen receptor alpha complexed to a substituted ligand
Structure: Estrogen receptor. Chain: a, b. Fragment: residues 298-554. Synonym: er, estradiol receptor, er-alpha. Engineered: yes. Mutation: yes. Grip peptide. Chain: c, d. Fragment: residues 696-698.
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: esr1, esr, nr3a1. Expressed in: escherichia coli. Expression_system_taxid: 562. Mus musculus. House mouse. Organism_taxid: 10090.
2.70Å     R-factor:   0.231     R-free:   0.297
Authors: H.Zhou,K.W.Nettles,J.B.Bruning,Y.Kim,A.Joachimiak,S.Sharma, K.E.Carlson,F.Stossi,B.S.Katzenellenbogen,G.L.Greene, J.A.Katzenellenbogen
Key ref:
H.B.Zhou et al. (2007). Elemental isomerism: a boron-nitrogen surrogate for a carbon-carbon double bond increases the chemical diversity of estrogen receptor ligands. Chem Biol, 14, 659-669. PubMed id: 17584613 DOI: 10.1016/j.chembiol.2007.04.009
05-Jun-07     Release date:   26-Jun-07    
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Protein chains
Pfam   ArchSchema ?
P03372  (ESR1_HUMAN) -  Estrogen receptor
595 a.a.
242 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: 10.1016/j.chembiol.2007.04.009 Chem Biol 14:659-669 (2007)
PubMed id: 17584613  
Elemental isomerism: a boron-nitrogen surrogate for a carbon-carbon double bond increases the chemical diversity of estrogen receptor ligands.
H.B.Zhou, K.W.Nettles, J.B.Bruning, Y.Kim, A.Joachimiak, S.Sharma, K.E.Carlson, F.Stossi, B.S.Katzenellenbogen, G.L.Greene, J.A.Katzenellenbogen.
To increase the chemical diversity of bioactive molecules by incorporating unusual elements, we have examined the replacement of a C=C double bond with the isoelectronic, isostructural B-N bond in the context of nonsteroidal estrogen receptor (ER) ligands. While the B-N bond was hydrolytically labile in the unhindered cyclofenil system, the more hindered anilino dimesitylboranes, analogs of triarylethylene estrogens, were easily prepared, hydrolytically stable, and demonstrated substantial affinity for ERs. X-ray analysis of one ERalpha-ligand complex revealed steric clashes with the para methyl groups distorting the receptor; removal of these groups resulted in an increase in affinity, potency, and transcriptional efficacy. These studies define the structural determinants of stability and cellular bioactivity of a B-N for C=C substitution in nonsteroidal estrogens and provide a framework for further exploration of "elemental isomerism" for diversification of drug-like molecules.
  Selected figure(s)  
Figure 2.
Figure 2. B-N Bond for C=C Bond Replacement and Di- and Triarylethylene
Comparison of π-bond systems, resonance forms, proposed mechanism of B-N hydrolysis, and nonsteroidal estrogens and their B-N analogs.
Figure 5.
Figure 5. X-Ray Structure of Compound 9e Bound to ERα
(A) The ligand-binding domain of ERα is shown as a ribbon diagram; the bound compound 9e is shown as a stick figure.
(B) Comparison of the X-ray crystallographic structure of anilino dimesitylborane (9e) complexed with ERα-ligand-binding domain with the diethylstilbestrol (DES) ERα structure [28]. The compound 9e-ER structure is atom color coded by CPK; the ligand and selected residues in the pocket are shown. For the ligand, the boron is colored purple, and the fluorines are colored green. The DES molecule is colored green, and the corresponding ER amino acids are colored yellow. The structures were superimposed over all backbone residues by using SwissPDBViewer.
  The above figures are reprinted by permission from Cell Press: Chem Biol (2007, 14, 659-669) copyright 2007.  
  Figures were selected by the author.  
    Author's comment    
  This figure illustrated how the boron-nitrogen compound fits into the ligand binding sites of the estrogen receptor, and, in particular, guided further optimization of compounds in this series. Notable, was the fact that the methyl groups at the para position on the two phenyl groups interfered with optimal ligand binding - one interacted with A350, preventing the ligand from entering the binding pocket fully, and the other pushed against residues in helix-11, destabilizing the agonist conformation. On the basis of these unfavorable interactions, it was predicted that removal of these two "offending methyl groups" would both raise binding affinity and increase agonist activity. In fact, both of these predictions were borne out; the bis-desmethyl compound had up to 20-fold higher affinity and greatly increased efficacy.  

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.  
20924370 J.B.Bruning, A.A.Parent, G.Gil, M.Zhao, J.Nowak, M.C.Pace, C.L.Smith, P.V.Afonine, P.D.Adams, J.A.Katzenellenbogen, and K.W.Nettles (2010).
Coupling of receptor conformation and ligand orientation determine graded activity.
  Nat Chem Biol, 6, 837-843.
PDB codes: 2qxs 2qzo 3os8 3os9 3osa
19823745 A.N.Lamm, and S.Y.Liu (2009).
How stable are 1,2-dihydro-1,2-azaborines toward water and oxygen?
  Mol Biosyst, 5, 1303-1305.  
19014882 H.B.Zhou, K.E.Carlson, F.Stossi, B.S.Katzenellenbogen, and J.A.Katzenellenbogen (2009).
Analogs of methyl-piperidinopyrazole (MPP): antiestrogens with estrogen receptor alpha selective activity.
  Bioorg Med Chem Lett, 19, 108-110.  
18344977 K.W.Nettles, J.B.Bruning, G.Gil, J.Nowak, S.K.Sharma, J.B.Hahm, K.Kulp, R.B.Hochberg, H.Zhou, J.A.Katzenellenbogen, B.S.Katzenellenbogen, Y.Kim, A.Joachmiak, and G.L.Greene (2008).
NFkappaB selectivity of estrogen receptor ligands revealed by comparative crystallographic analyses.
  Nat Chem Biol, 4, 241-247.
PDB codes: 2b23 2qa6 2qa8 2qab 2qgt 2qgw 2qh6 2qr9 2qse 2qxm
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