5TNB

Crystal Structure of the ER-alpha Ligand-binding Domain (L372S,L536S) in Complex with the OBHS-BSC, 4-bromophenyl (1R,2R,4S)-6-(4-(2-(dimethylamino)ethoxy)phenyl)-5-(4-hydroxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonate


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.08 Å
  • R-Value Free: 0.218 
  • R-Value Work: 0.188 
  • R-Value Observed: 0.189 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Exploring the Structural Compliancy versus Specificity of the Estrogen Receptor Using Isomeric Three-Dimensional Ligands.

Sharma, N.Carlson, K.E.Nwachukwu, J.C.Srinivasan, S.Sharma, A.Nettles, K.W.Katzenellenbogen, J.A.

(2017) ACS Chem Biol 12: 494-503

  • DOI: https://doi.org/10.1021/acschembio.6b00918
  • Primary Citation of Related Structures:  
    5TN9, 5TNB

  • PubMed Abstract: 

    The estrogen receptors (ERs) bind with high affinity to many structurally diverse ligands by significantly distorting the contours of their ligand-binding pockets. This raises a question: To what degree is ER able to distinguish between structurally related regioisomers and enantiomers? We have explored the structural compliance and specificity of ERα with a set of ligands having a 7-oxa-bicyclo[2.2.1]hept-5-ene sulfonate core and basic side chains typical of selective ER modulators (SERMs). These ligands have two regioisomers, each of which is a racemate of enantiomers. Using orthogonal protecting groups and chiral HPLC, we isolated all 4 isomers and assigned their absolute stereochemistry by X-ray analysis. The 1S,2R,4S isomer has a 80-170-fold higher affinity for ERα than the others, and it profiles as a partial agonist/antagonist in cellular reporter gene assays and in suppressing proliferation of MCF-7 breast cancer cells with subnanomolar potency, far exceeding that of the other isomers. It is the only isomer found bound to ERα by X-ray analysis after crystallization with four-isomer mixtures of closely related analogs. Thus, despite the general compliance of this receptor for binding a large variety of ligand structures, ER demonstrates marked structural specificity and stereospecificity by selecting a single component from a mixture of structurally related isomers to drive ER-regulated cellular activity. Our findings lay the necessary groundwork for seeking unique ER-mediated pharmacological profiles by rational structural perturbations of two different types of side chains in this unprecedented class of ER ligands, which may prove useful in developing more effective endocrine therapies for breast cancer.


  • Organizational Affiliation

    Department of Chemistry, University of Illinois at Urbana-Champaign , 600 South Mathews Avenue, Urbana, Illinois 61801, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Estrogen receptor
A, B, C, D
257Homo sapiensMutation(s): 2 
Gene Names: ESR1ESRNR3A1
UniProt & NIH Common Fund Data Resources
Find proteins for P03372 (Homo sapiens)
Explore P03372 
Go to UniProtKB:  P03372
PHAROS:  P03372
GTEx:  ENSG00000091831 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP03372
Sequence Annotations
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  • Reference Sequence
Small Molecules
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.08 Å
  • R-Value Free: 0.218 
  • R-Value Work: 0.188 
  • R-Value Observed: 0.189 
  • Space Group: P 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 53.549α = 86.5
b = 58.627β = 75.02
c = 94.304γ = 62.83
Software Package:
Software NamePurpose
HKL-2000data scaling
PHENIXrefinement
PDB_EXTRACTdata extraction
HKL-2000data reduction
PHENIXphasing
DENZOdata reduction
SCALEPACKdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2017-02-15
    Type: Initial release
  • Version 1.1: 2017-03-01
    Changes: Database references
  • Version 1.2: 2017-11-22
    Changes: Refinement description
  • Version 1.3: 2024-03-06
    Changes: Data collection, Database references