4XI3

Estrogen Receptor Alpha Ligand Binding Domain in Complex with Bazedoxifene


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.49 Å
  • R-Value Free: 0.268 
  • R-Value Work: 0.215 
  • R-Value Observed: 0.218 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

The SERM/SERD bazedoxifene disrupts ESR1 helix 12 to overcome acquired hormone resistance in breast cancer cells.

Fanning, S.W.Jeselsohn, R.Dharmarajan, V.Mayne, C.G.Karimi, M.Buchwalter, G.Houtman, R.Toy, W.Fowler, C.E.Han, R.Laine, M.Carlson, K.E.Martin, T.A.Nowak, J.Nwachukwu, J.C.Hosfield, D.J.Chandarlapaty, S.Tajkhorshid, E.Nettles, K.W.Griffin, P.R.Shen, Y.Katzenellenbogen, J.A.Brown, M.Greene, G.L.

(2018) Elife 7

  • DOI: https://doi.org/10.7554/eLife.37161
  • Primary Citation of Related Structures:  
    4XI3

  • PubMed Abstract: 

    Acquired resistance to endocrine therapy remains a significant clinical burden for breast cancer patients. Somatic mutations in the ESR1 (estrogen receptor alpha (ERα)) gene ligand-binding domain (LBD) represent a recognized mechanism of acquired resistance. Antiestrogens with improved efficacy versus tamoxifen might overcome the resistant phenotype in ER +breast cancers. Bazedoxifene (BZA) is a potent antiestrogen that is clinically approved for use in hormone replacement therapies. We found that BZA possesses improved inhibitory potency against the Y537S and D538G ERα mutants compared to tamoxifen and has additional inhibitory activity in combination with the CDK4/6 inhibitor palbociclib. In addition, comprehensive biophysical and structural biology studies show BZA's selective estrogen receptor degrading (SERD) properties that override the stabilizing effects of the Y537S and D538G ERα mutations.


  • Organizational Affiliation

    Ben May Department for Cancer Research, University of Chicago, Chicago, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Estrogen receptor
A, B, C, D
243Homo 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
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.49 Å
  • R-Value Free: 0.268 
  • R-Value Work: 0.215 
  • R-Value Observed: 0.218 
  • Space Group: P 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 53.575α = 86.76
b = 59.165β = 75.36
c = 94.144γ = 63.03
Software Package:
Software NamePurpose
PHENIXrefinement
HKL-3000data reduction
HKL-3000data scaling
HKL-3000phasing
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Department of Defense (DOD, United States)United StatesBC131458P1

Revision History  (Full details and data files)

  • Version 1.0: 2016-01-13
    Type: Initial release
  • Version 1.1: 2019-04-10
    Changes: Author supporting evidence, Data collection, Derived calculations, Structure summary
  • Version 1.2: 2019-11-27
    Changes: Author supporting evidence
  • Version 1.3: 2023-09-27
    Changes: Data collection, Database references, Refinement description
  • Version 1.4: 2024-03-06
    Changes: Advisory, Database references, Derived calculations