5GTR

estrogen receptor alpha in complex with a stabilized peptide antagonist 6


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.80 Å
  • R-Value Free: 0.367 
  • R-Value Work: 0.221 
  • R-Value Observed: 0.228 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Structural Basis of Inhibition of ER alpha-Coactivator Interaction by High-Affinity N-Terminus Isoaspartic Acid Tethered Helical Peptides

Xie, M.Zhao, H.Liu, Q.Zhu, Y.Yin, F.Liang, Y.Jiang, Y.Wang, D.Hu, K.Qin, X.Wang, Z.Wu, Y.Xu, N.Ye, X.Wang, T.Li, Z.

(2017) J Med Chem 60: 8731-8740

  • DOI: https://doi.org/10.1021/acs.jmedchem.7b00732
  • Primary Citation of Related Structures:  
    5GS4, 5GTR

  • PubMed Abstract: 

    Direct inhibition of the protein-protein interaction of ERα and its endogenous coactivators with a cell permeable stabilized peptide may offer a novel, promising strategy for combating ERα positive breast cancers. Here, we report the co-crystal structure of a helical peptide stabilized by a N-terminal unnatural cross-linked aspartic acid (TD) in complex with the ERα ligand binding domain (LBD). We designed a series of peptides and peptide 6 that showed direct and high-affinity binding to ERα with selective antiproliferative activity in ERα positive breast cancer cells. The co-crystal structure of the TD-stabilized peptide 6 in complex with ERα LBD further demonstrates that it forms an α helical conformation and directly binds at the coactivator binding site of ERα. Further studies showed that peptide 6 W could potently inhibit cellular ERα's transcriptional activity. This approach demonstrates the potential of TD stabilized peptides to modulate various intracellular protein-protein interactions involved in a range of disorders.


  • Organizational Affiliation

    School of Chemical Biology and Biotechnology, Shenzhen Graduate School of Peking University , Shenzhen 518055, China.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Estrogen receptor243Homo sapiensMutation(s): 0 
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

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
ARG-IAS-ILE-0JY-DPP-ARG-0JY-0JY-GLN-NH2B [auth C]10unidentifiedMutation(s): 0 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
EST
Query on EST

Download Ideal Coordinates CCD File 
C [auth A]ESTRADIOL
C18 H24 O2
VOXZDWNPVJITMN-ZBRFXRBCSA-N
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
DPP
Query on DPP
B [auth C]L-PEPTIDE LINKINGC3 H8 N2 O2ALA
Binding Affinity Annotations 
IDSourceBinding Affinity
EST BindingDB:  5GTR Ki: min: 0.11, max: 100 (nM) from 13 assay(s)
Kd: min: 0.2, max: 100 (nM) from 4 assay(s)
IC50: min: 1.00e-2, max: 46 (nM) from 46 assay(s)
EC50: min: 4.00e-3, max: 10 (nM) from 52 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.80 Å
  • R-Value Free: 0.367 
  • R-Value Work: 0.221 
  • R-Value Observed: 0.228 
  • Space Group: P 2 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 54.787α = 90
b = 60.219β = 90
c = 66.457γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
HKL-3000data reduction
HKL-3000data scaling
PHENIXphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Natural Science Foundation of ChinaChina21102007 and 21372023

Revision History  (Full details and data files)

  • Version 1.0: 2017-08-30
    Type: Initial release
  • Version 1.1: 2017-09-27
    Changes: Data collection
  • Version 1.2: 2017-12-20
    Changes: Database references