5EXA

Small-molecule stabilization of the 14-3-3/Gab2 PPI interface


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.234 
  • R-Value Work: 0.198 
  • R-Value Observed: 0.200 

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Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Small-Molecule Stabilization of the 14-3-3/Gab2 Protein-Protein Interaction (PPI) Interface.

Bier, D.Bartel, M.Sies, K.Halbach, S.Higuchi, Y.Haranosono, Y.Brummer, T.Kato, N.Ottmann, C.

(2016) ChemMedChem 11: 911-918

  • DOI: https://doi.org/10.1002/cmdc.201500484
  • Primary Citation of Related Structures:  
    5EWZ, 5EXA

  • PubMed Abstract: 

    Small-molecule modulation of protein-protein interactions (PPIs) is one of the most promising new areas in drug discovery. In the vast majority of cases only inhibition or disruption of PPIs is realized, whereas the complementary strategy of targeted stabilization of PPIs is clearly under-represented. Here, we report the example of a semi-synthetic natural product derivative--ISIR-005--that stabilizes the cancer-relevant interaction of the adaptor protein 14-3-3 and Gab2. The crystal structure of ISIR-005 in complex with 14-3-3 and the binding motif of Gab2 comprising two phosphorylation sites (Gab2pS210pT391) showed how the stabilizing molecule binds to the rim-of-the-interface of the protein complex. Only in the direct vicinity of 14-3-3/Gab2pT391 site is a pre-formed pocket occupied by ISIR-005; binding of the Gab2pS210 motif to 14-3-3 does not create an interface pocket suitable for the molecule. Accordingly, ISIR-005 only stabilizes the binding of the Gab2pT391 but not the Gab2pS210 site. This study represents structural and biochemical proof of the druggability of the 14-3-3/Gab2 PPI interface with important implications for the development of PPI stabilizers.


  • Organizational Affiliation

    Department of Chemistry, University of Duisburg-Essen, Universitätstr. 7, 45141, Essen, Germany.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
14-3-3 protein zeta/delta
A, B
230Homo sapiensMutation(s): 0 
Gene Names: YWHAZ
UniProt & NIH Common Fund Data Resources
Find proteins for P63104 (Homo sapiens)
Explore P63104 
Go to UniProtKB:  P63104
PHAROS:  P63104
GTEx:  ENSG00000164924 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP63104
Sequence Annotations
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  • Reference Sequence

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
GRB2-associated-binding protein 2
C, D
11Homo sapiensMutation(s): 0 
UniProt & NIH Common Fund Data Resources
Find proteins for Q9UQC2 (Homo sapiens)
Explore Q9UQC2 
Go to UniProtKB:  Q9UQC2
PHAROS:  Q9UQC2
GTEx:  ENSG00000033327 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9UQC2
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.234 
  • R-Value Work: 0.198 
  • R-Value Observed: 0.200 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 72α = 90
b = 83.09β = 90
c = 111.15γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
XSCALEdata scaling
PHASERphasing
PDB_EXTRACTdata extraction

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2016-05-04
    Type: Initial release
  • Version 1.1: 2018-12-19
    Changes: Data collection, Derived calculations