PDBsum entry 2r6w

Go to PDB code: 
protein ligands Protein-protein interface(s) links
Transcription PDB id
Protein chains
229 a.a. *
LLB ×2
Waters ×104
* Residue conservation analysis
PDB id:
Name: Transcription
Title: Estrogen receptor alpha ligand-binding domain complexed to a serm
Structure: Estrogen receptor. Chain: a, b. Fragment: ligand binding domain, unp residues 304-551. Synonym: er, estradiol receptor, er-alpha. Engineered: yes. Mutation: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: esr1, esr, nr3a1. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
2.00Å     R-factor:   0.212     R-free:   0.257
Authors: Y.Wang
Key ref:
S.Y.Dai et al. (2008). Prediction of the tissue-specificity of selective estrogen receptor modulators by using a single biochemical method. Proc Natl Acad Sci U S A, 105, 7171-7176. PubMed id: 18474858 DOI: 10.1073/pnas.0710802105
06-Sep-07     Release date:   08-Apr-08    
Go to PROCHECK summary

Protein chains
Pfam   ArchSchema ?
P03372  (ESR1_HUMAN) -  Estrogen receptor
595 a.a.
229 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     3 terms  


DOI no: 10.1073/pnas.0710802105 Proc Natl Acad Sci U S A 105:7171-7176 (2008)
PubMed id: 18474858  
Prediction of the tissue-specificity of selective estrogen receptor modulators by using a single biochemical method.
S.Y.Dai, M.J.Chalmers, J.Bruning, K.S.Bramlett, H.E.Osborne, C.Montrose-Rafizadeh, R.J.Barr, Y.Wang, M.Wang, T.P.Burris, J.A.Dodge, P.R.Griffin.
Here, we demonstrate that a single biochemical assay is able to predict the tissue-selective pharmacology of an array of selective estrogen receptor modulators (SERMs). We describe an approach to classify estrogen receptor (ER) modulators based on dynamics of the receptor-ligand complex as probed with hydrogen/deuterium exchange (HDX) mass spectrometry. Differential HDX mapping coupled with cluster and discriminate analysis effectively predicted tissue-selective function in most, but not all, cases tested. We demonstrate that analysis of dynamics of the receptor-ligand complex facilitates binning of ER modulators into distinct groups based on structural dynamics. Importantly, we were able to differentiate small structural changes within ER ligands of the same chemotype. In addition, HDX revealed differentially stabilized regions within the ligand-binding pocket that may contribute to the different pharmacology phenotypes of the compounds independent of helix 12 positioning. In summary, HDX provides a sensitive and rapid approach to classify modulators of the estrogen receptor that correlates with their pharmacological profile.
  Selected figure(s)  
Figure 1.
Cluster analysis of known compounds. The names of the compound are shown above the bar view, and peptide regions that have been used for cluster analysis are shown on the right of the bar view. The deuterium incorporation differences of these peptides have been treated as independent variables, and each compound has been treated as a dependent variables in the cluster analysis. The color represents the differential deuterium level of each peptide in the absence and presence of the compound. The 4-hydroxytamoxifen was abbreviated as 4-OH-Tam.
Figure 2.
ER-ligand HDX profiles. (A–C). HDX profile overlaid onto ER crystal structures of estradiol (PDB ID: 1ERE), 4-hydroxytamoxifen (PDB ID: 3ERT, the 4-hydroxytamoxifen was abbreviated as 4-OH-tamoxifen), and raloxifene (PDB ID: 1ERR). (D and E). HDX profile overlaid onto ER crystal structure with LY156681 and LY117018. The color legend shows the deuterium incorporation difference by subtracting deuterium incorporation content of holo ER from apo ER. The regions in the crystal structure that are colored as white belong to peptides that are not detected after pepsin digestion or cannot be measured accurately in the HDX experiments because of coelution problems.

Literature references that cite this PDB file's key reference

  PubMed id Reference
21331802 A.Bujotzek, M.Shan, R.Haag, and M.Weber (2011).
Towards a rational spacer design for bivalent inhibition of estrogen receptor.
  J Comput Aided Mol Des, 25, 253-262.  
21220114 E.Wright, S.A.Busby, S.Wisecarver, J.Vincent, P.R.Griffin, and E.J.Fernandez (2011).
Helix 11 dynamics is critical for constitutive androstane receptor activity.
  Structure, 19, 37-44.  
21291543 F.Liu, J.A.White, C.Antonescu, D.Gusenleitner, and J.Quackenbush (2011).
GCOD - GeneChip Oncology Database.
  BMC Bioinformatics, 12, 46.  
21478866 J.Zhang, M.J.Chalmers, K.R.Stayrook, L.L.Burris, Y.Wang, S.A.Busby, B.D.Pascal, R.D.Garcia-Ordonez, J.B.Bruning, M.A.Istrate, D.J.Kojetin, J.A.Dodge, T.P.Burris, and P.R.Griffin (2011).
DNA binding alters coactivator interaction surfaces of the intact VDR-RXR complex.
  Nat Struct Mol Biol, 18, 556-563.  
  21528013 M.J.Chalmers, B.D.Pascal, S.Willis, J.Zhang, S.J.Iturria, J.A.Dodge, and P.R.Griffin (2011).
Methods for the Analysis of High Precision Differential Hydrogen Deuterium Exchange Data.
  Int J Mass Spectrom, 302, 59-68.  
21329427 M.J.Chalmers, S.A.Busby, B.D.Pascal, G.M.West, and P.R.Griffin (2011).
Differential hydrogen/deuterium exchange mass spectrometry analysis of protein-ligand interactions.
  Expert Rev Proteomics, 8, 43-59.  
21342575 S.Liu, L.Liu, U.Uzuner, X.Zhou, M.Gu, W.Shi, Y.Zhang, S.Y.Dai, and J.S.Yuan (2011).
HDX-analyzer: a novel package for statistical analysis of protein structure dynamics.
  BMC Bioinformatics, 12, S43.  
20122183 S.Mitra, M.Schubach, and D.H.Huson (2010).
Short clones or long clones? A simulation study on the use of paired reads in metagenomics.
  BMC Bioinformatics, 11, S12.  
20058880 X.Zhang, E.Y.Chien, M.J.Chalmers, B.D.Pascal, J.Gatchalian, R.C.Stevens, and P.R.Griffin (2010).
Dynamics of the beta2-adrenergic G-protein coupled receptor revealed by hydrogen-deuterium exchange.
  Anal Chem, 82, 1100-1108.  
19135386 B.D.Pascal, M.J.Chalmers, S.A.Busby, and P.R.Griffin (2009).
HD desktop: an integrated platform for the analysis and visualization of H/D exchange data.
  J Am Soc Mass Spectrom, 20, 601-610.  
19574232 J.L.Lauer-Fields, M.J.Chalmers, S.A.Busby, D.Minond, P.R.Griffin, and G.B.Fields (2009).
Identification of specific hemopexin-like domain residues that facilitate matrix metalloproteinase collagenolytic activity.
  J Biol Chem, 284, 24017-24024.  
19739677 S.Y.Dai, T.P.Burris, J.A.Dodge, C.Montrose-Rafizadeh, Y.Wang, B.D.Pascal, M.J.Chalmers, and P.R.Griffin (2009).
Unique ligand binding patterns between estrogen receptor alpha and beta revealed by hydrogen-deuterium exchange.
  Biochemistry, 48, 9668-9676.  
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.