5DXE

Estrogen Receptor Alpha Ligand Binding Domain Y537S Mutant in Complex with Stapled Peptide SRC2-P4 and Estradiol

  • Classification: Hormone receptor/peptide
  • Organism(s): Homo sapiens
  • Expression System: Escherichia coli
  • Mutation(s): Yes 

  • Deposited: 2015-09-23 Released: 2016-08-03 
  • Deposition Author(s): Fanning, S.W., Speltz, T.E., Mayne, C.G., Tajkhorshid, E., Greene, G.L., Moore, T.W.
  • Funding Organization(s): American Association of Colleges of Pharmacy, University of Illinois Cancer Center, Chicago Biomedical Consortium, National Institutes of Health/Office of the Director, National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS), National Science Foundation (NSF, United States), National Institutes of Health/National Center for Complementary and Integrative Health (NIH/NCCIH)

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.50 Å
  • R-Value Free: 0.201 
  • R-Value Work: 0.178 
  • R-Value Observed: 0.179 

Starting Model: experimental
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wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.7 of the entry. See complete history


Literature

Stapled Peptides with gamma-Methylated Hydrocarbon Chains for the Estrogen Receptor/Coactivator Interaction.

Speltz, T.E.Fanning, S.W.Mayne, C.G.Fowler, C.Tajkhorshid, E.Greene, G.L.Moore, T.W.

(2016) Angew Chem Int Ed Engl 55: 4252-4255

  • DOI: https://doi.org/10.1002/anie.201510557
  • Primary Citation of Related Structures:  
    5DX3, 5DXB, 5DXE, 5DXG, 5HYR

  • PubMed Abstract: 

    "Stapled" peptides are typically designed to replace two non-interacting residues with a constraining, olefinic staple. To mimic interacting leucine and isoleucine residues, we have created new amino acids that incorporate a methyl group in the γ-position of the stapling amino acid S5. We have incorporated them into a sequence derived from steroid receptor coactivator 2, which interacts with estrogen receptor α. The best peptide (IC50 =89 nm) replaces isoleucine 689 with an S-γ-methyl stapled amino acid, and has significantly higher affinity than unsubstituted peptides (390 and 760 nm). Through X-ray crystallography and molecular dynamics studies, we show that the conformation taken up by the S-γ-methyl peptide minimizes the syn-pentane interactions between the α- and γ-methyl groups.


  • Organizational Affiliation

    Department of Medicinal Chemistry and Pharmacognosy and UI Cancer Center, University of Illinois at Chicago, 833 S. Wood St., Chicago, IL, 60612, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Estrogen receptor
A, B
261Homo 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
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  • Reference Sequence

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Nuclear receptor coactivator 2
C, D
13Homo 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
Modified Residues  2 Unique
IDChains TypeFormula2D DiagramParent
SCH
Query on SCH
A, B
L-PEPTIDE LINKINGC4 H9 N O2 S2CYS
MK8
Query on MK8
C, D
L-PEPTIDE LINKINGC7 H15 N O2LEU
Binding Affinity Annotations 
IDSourceBinding Affinity
EST BindingDB:  5DXE Ki: min: 0.11, max: 100 (nM) from 14 assay(s)
Kd: min: 0.2, max: 3.5 (nM) from 3 assay(s)
IC50: min: 1.00e-2, max: 46 (nM) from 50 assay(s)
EC50: min: 4.00e-3, max: 10 (nM) from 53 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.50 Å
  • R-Value Free: 0.201 
  • R-Value Work: 0.178 
  • R-Value Observed: 0.179 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 56.009α = 90
b = 85.181β = 108.64
c = 58.291γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
HKL-3000data reduction
HKL-3000data scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
American Association of Colleges of PharmacyUnited States--
University of Illinois Cancer CenterUnited States--
Chicago Biomedical ConsortiumUnited States--
National Institutes of Health/Office of the DirectorUnited StatesT32 AT007533
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)United StatesP41-GM10461
National Science Foundation (NSF, United States)United StatesMCA06N060
National Institutes of Health/National Center for Complementary and Integrative Health (NIH/NCCIH)United States--

Revision History  (Full details and data files)

  • Version 1.0: 2016-08-03
    Type: Initial release
  • Version 1.1: 2017-09-06
    Changes: Author supporting evidence, Database references, Derived calculations
  • Version 1.2: 2017-09-27
    Changes: Author supporting evidence
  • Version 1.3: 2019-11-27
    Changes: Author supporting evidence
  • Version 1.4: 2020-02-19
    Changes: Derived calculations
  • Version 1.5: 2020-03-11
    Changes: Derived calculations
  • Version 1.6: 2023-09-27
    Changes: Data collection, Database references, Refinement description
  • Version 1.7: 2023-11-15
    Changes: Data collection