4DX0

Structure of the 14-3-3/PMA2 complex stabilized by a pyrazole derivative


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.40 Å
  • R-Value Free: 0.399 
  • R-Value Work: 0.356 
  • R-Value Observed: 0.358 

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This is version 1.2 of the entry. See complete history


Literature

An Optimised Small-Molecule Stabiliser of the 14-3-3-PMA2 Protein-Protein Interaction.

Richter, A.Rose, R.Hedberg, C.Waldmann, H.Ottmann, C.

(2012) Chemistry 18: 6520-6527

  • DOI: https://doi.org/10.1002/chem.201103761
  • Primary Citation of Related Structures:  
    4DX0

  • PubMed Abstract: 

    Modulation of protein-protein interactions (PPIs) is a highly demanding, but also a very promising approach in chemical biology and targeted drug discovery. In contrast to inhibiting PPIs with small, chemically tractable molecules, stabilisation of these interactions can only be achieved with complex natural products, like rapamycin, FK506, taxol, forskolin, brefeldin and fusicoccin. Fusicoccin stabilises the activatory complex of the plant H(+)-ATPase PMA2 and 14-3-3 proteins. Recently, we have shown that the stabilising effect of fusicoccin could be mimicked by a trisubstituted pyrrolinone (pyrrolidone1, 1). Here, we report the synthesis, functional activity and crystal structure of derivatives of 1 that stabilise the 14-3-3-PMA2 complex. With a limited compound collection three modifications that are important for activity enhancement could be determined: 1) conversion of the pyrrolinone scaffold into a pyrazole, 2) introduction of a tetrazole moiety to the phenyl ring that contacts PMA2, and 3) addition of a bromine to the phenyl ring that exclusively contacts the 14-3-3 protein. The crystal structure of a pyrazole derivative of 1 in complex with 14-3-3 and PMA2 revealed that the more rigid core of this molecule positions the stabiliser deeper into the rim of the interface, enlarging especially the contact surface to PMA2. Combination of the aforementioned features gave rise to a molecule (37) that displays a threefold increase in stabilising the 14-3-3-PMA2 complex over 1. Compound 37 and the other active derivatives show no effect on two other important 14-3-3 protein-protein interactions, that is, with CRaf and p53. This is the first study that describes the successful optimisation of a PPI stabiliser identified by screening.


  • Organizational Affiliation

    Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
14-3-3-like protein E243Nicotiana tabacumMutation(s): 0 
UniProt
Find proteins for O49997 (Nicotiana tabacum)
Explore O49997 
Go to UniProtKB:  O49997
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO49997
Sequence Annotations
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  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
N.plumbaginifolia H+-translocating ATPase mRNAB [auth P]31Nicotiana plumbaginifoliaMutation(s): 2 
EC: 3.6.3.6
UniProt
Find proteins for Q42932 (Nicotiana plumbaginifolia)
Explore Q42932 
Go to UniProtKB:  Q42932
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ42932
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
0MT
Query on 0MT

Download Ideal Coordinates CCD File 
C [auth A]4-[(4R)-4-(4-nitrophenyl)-6-oxidanylidene-3-phenyl-1,4-dihydropyrrolo[3,4-c]pyrazol-5-yl]benzoic acid
C24 H16 N4 O5
FAPWESYGTXHTQV-JOCHJYFZSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.40 Å
  • R-Value Free: 0.399 
  • R-Value Work: 0.356 
  • R-Value Observed: 0.358 
  • Space Group: I 41 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 98.45α = 90
b = 98.45β = 90
c = 216.71γ = 90
Software Package:
Software NamePurpose
XSCALEdata scaling
PHASERphasing
DMphasing
REFMACrefinement
PDB_EXTRACTdata extraction
XDSdata scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2012-05-30
    Type: Initial release
  • Version 1.1: 2023-09-13
    Changes: Data collection, Database references, Derived calculations, Refinement description
  • Version 1.2: 2023-12-13
    Changes: Derived calculations