5UFX

Estrogen Receptor Alpha Ligand Binding Domain in Complex with OP1074


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.55 Å
  • R-Value Free: 0.230 
  • R-Value Work: 0.195 
  • R-Value Observed: 0.197 

Starting Model: experimental
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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Specific stereochemistry of OP-1074 disrupts estrogen receptor alpha helix 12 and confers pure antiestrogenic activity.

Fanning, S.W.Hodges-Gallagher, L.Myles, D.C.Sun, R.Fowler, C.E.Plant, I.N.Green, B.D.Harmon, C.L.Greene, G.L.Kushner, P.J.

(2018) Nat Commun 9: 2368-2368

  • DOI: https://doi.org/10.1038/s41467-018-04413-3
  • Primary Citation of Related Structures:  
    5UFW, 5UFX, 6C42

  • PubMed Abstract: 

    Complex tissue-specific and cell-specific signaling by the estrogen receptor (ER) frequently leads to the development of resistance to endocrine therapy for breast cancer. Pure ER antagonists, which completely lack tissue-specific agonist activity, hold promise for preventing and treating endocrine resistance, however an absence of structural information hinders the development of novel candidates. Here we synthesize a small panel of benzopyrans with variable side chains to identify pure antiestrogens in a uterotrophic assay. We identify OP-1074 as a pure antiestrogen and a selective ER degrader (PA-SERD) that is efficacious in shrinking tumors in a tamoxifen-resistant xenograft model. Biochemical and crystal structure analyses reveal a structure activity relationship implicating the importance of a stereospecific methyl on the pyrrolidine side chain of OP-1074, particularly on helix 12.


  • Organizational Affiliation

    Ben May Department for Cancer Research, University of Chicago, Chicago, IL, 60637, USA. [email protected].


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Estrogen receptor
A, B
249Homo sapiensMutation(s): 4 
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
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
86Y
Query on 86Y

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
(2S)-3-(4-hydroxyphenyl)-4-methyl-2-(4-{2-[(3R)-3-methylpyrrolidin-1-yl]ethoxy}phenyl)-2H-1-benzopyran-7-ol
C29 H31 N O4
KDVXAPCZVZMPMU-XBBWARJSSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.55 Å
  • R-Value Free: 0.230 
  • R-Value Work: 0.195 
  • R-Value Observed: 0.197 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 102.722α = 90
b = 58.015β = 102.89
c = 87.834γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
PHENIXdata reduction
PHENIXdata scaling
PHENIXphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2018-01-10
    Type: Initial release
  • Version 1.1: 2018-06-27
    Changes: Data collection, Database references
  • Version 1.2: 2023-10-04
    Changes: Advisory, Data collection, Database references, Refinement description