4J24

Estrogen Receptor in complex with proline-flanked LXXLL peptides


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.224 
  • R-Value Work: 0.190 
  • R-Value Observed: 0.192 

Starting Model: experimental
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This is version 1.2 of the entry. See complete history


Literature

Proline primed helix length as a modulator of the nuclear receptor-coactivator interaction

Fuchs, S.Nguyen, H.D.Phan, T.T.Burton, M.F.Nieto, L.de Vries-van Leeuwen, I.J.Schmidt, A.Goodarzifard, M.Agten, S.M.Rose, R.Ottmann, C.Milroy, L.G.Brunsveld, L.

(2013) J Am Chem Soc 135: 4364-4371

  • DOI: https://doi.org/10.1021/ja311748r
  • Primary Citation of Related Structures:  
    4J24, 4J26

  • PubMed Abstract: 

    Nuclear receptor binding to coactivator proteins is an obligate first step in the regulation of gene transcription. Nuclear receptors preferentially bind to an LXXLL peptide motif which is highly conserved throughout the 300 or so natural coactivator proteins. This knowledge has shaped current understanding of this fundamental protein-protein interaction, and continues to inspire the search for new drug therapies. However, sequence specificity beyond the LXXLL motif and the molecular functioning of flanking residues still requires urgent addressing. Here, ribosome display has been used to reassess the estrogen receptor for new and enlarged peptide recognition motifs, leading to the discovery of a potent and highly evolved PXLXXLLXXP binding consensus. Molecular modeling and X-ray crystallography studies have provided the molecular insights on the role of the flanking prolines in priming the length of the α-helix and enabling optimal interactions of the α-helix dipole and its surrounding amino acids with the surface charge clamp and the receptor activation function 2. These findings represent new structural parameters for modulating the nuclear receptor-coactivator interaction based on linear sequences of proteinogenic amino acids and for the design of chemically modified inhibitors.


  • Organizational Affiliation

    Laboratory of Chemical Biology, Department of Biomedical Engineering, Technische Universiteit Eindhoven, Den Dolech 2, 5612 AZ Eindhoven, The Netherlands.


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Estrogen receptor beta
A, B, C, D
240Homo sapiensMutation(s): 0 
Gene Names: ESR2
UniProt & NIH Common Fund Data Resources
Find proteins for Q92731 (Homo sapiens)
Explore Q92731 
Go to UniProtKB:  Q92731
PHAROS:  Q92731
GTEx:  ENSG00000140009 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ92731
Sequence Annotations
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  • Reference Sequence

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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
19-mer peptideE [auth K],
F [auth I],
G [auth J],
H [auth L]
19N/AMutation(s): 0 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations
Expand
  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.224 
  • R-Value Work: 0.190 
  • R-Value Observed: 0.192 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 192.98α = 90
b = 53.49β = 120.47
c = 131.39γ = 90
Software Package:
Software NamePurpose
MAR345dtbdata collection
PHASERphasing
REFMACrefinement
XDSdata reduction
XSCALEdata scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2013-03-13
    Type: Initial release
  • Version 1.1: 2013-07-10
    Changes: Database references
  • Version 1.2: 2023-11-08
    Changes: Data collection, Database references, Derived calculations, Refinement description