5KCC

Crystal Structure of the ER-alpha Ligand-binding Domain (Y537S) in Complex with Oxabicyclic Heptene Sulfonamide (OBHS-N)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.39 Å
  • R-Value Free: 0.265 
  • R-Value Work: 0.224 
  • R-Value Observed: 0.229 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Full antagonism of the estrogen receptor without a prototypical ligand side chain.

Srinivasan, S.Nwachukwu, J.C.Bruno, N.E.Dharmarajan, V.Goswami, D.Kastrati, I.Novick, S.Nowak, J.Cavett, V.Zhou, H.B.Boonmuen, N.Zhao, Y.Min, J.Frasor, J.Katzenellenbogen, B.S.Griffin, P.R.Katzenellenbogen, J.A.Nettles, K.W.

(2017) Nat Chem Biol 13: 111-118

  • DOI: https://doi.org/10.1038/nchembio.2236
  • Primary Citation of Related Structures:  
    5KCC, 5KCD, 5KCE, 5KCF, 5KCT, 5KCU, 5KCW, 5KD9

  • PubMed Abstract: 

    Resistance to endocrine therapies remains a major clinical problem for the treatment of estrogen receptor-α (ERα)-positive breast cancer. On-target side effects limit therapeutic compliance and use for chemoprevention, highlighting an unmet need for new therapies. Here we present a full-antagonist ligand series lacking the prototypical ligand side chain that has been universally used to engender antagonism of ERα through poorly understood structural mechanisms. A series of crystal structures and phenotypic assays reveal a structure-based design strategy with separate design elements for antagonism and degradation of the receptor, and access to a structurally distinct space for further improvements in ligand design. Understanding structural rules that guide ligands to produce diverse ERα-mediated phenotypes has broad implications for the treatment of breast cancer and other estrogen-sensitive aspects of human health including bone homeostasis, energy metabolism, and autoimmunity.


  • Organizational Affiliation

    Department of Cancer Biology, The Scripps Research Institute, Jupiter, Florida, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Estrogen receptor
A, B
257Homo sapiensMutation(s): 1 
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
Expand
  • Reference Sequence

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
NCOA2
C, D
14Homo sapiensMutation(s): 0 
UniProt & NIH Common Fund Data Resources
Find proteins for Q15596 (Homo sapiens)
Explore Q15596 
Go to UniProtKB:  Q15596
PHAROS:  Q15596
GTEx:  ENSG00000140396 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ15596
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
OB1
Query on OB1

Download Ideal Coordinates CCD File 
E [auth A],
F [auth B]
(1S,2R,4S)-5,6-bis(4-hydroxyphenyl)-N-phenyl-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonamide
C24 H21 N O5 S
HRIRAPQMJVLREA-YZUZCNPQSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.39 Å
  • R-Value Free: 0.265 
  • R-Value Work: 0.224 
  • R-Value Observed: 0.229 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 54.53α = 90
b = 81.16β = 110.8
c = 58.68γ = 90
Software Package:
Software NamePurpose
HKL-2000data scaling
PHENIXrefinement
PDB_EXTRACTdata extraction
HKL-2000data reduction
PHENIXphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2016-11-16
    Type: Initial release
  • Version 1.1: 2016-12-21
    Changes: Database references
  • Version 1.2: 2016-12-28
    Changes: Database references
  • Version 1.3: 2020-02-26
    Changes: Derived calculations
  • Version 1.4: 2024-03-06
    Changes: Data collection, Database references