4DIJ

The Central Valine Concept Provides an Entry in a New Class of Non Peptide Inhibitors of the P53-MDM2 Interaction


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.224 
  • R-Value Work: 0.194 
  • R-Value Observed: 0.195 

Starting Model: other
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Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

The central valine concept provides an entry in a new class of non peptide inhibitors of the p53-MDM2 interaction.

Furet, P.Chene, P.De Pover, A.Valat, T.S.Lisztwan, J.H.Kallen, J.Masuya, K.

(2012) Bioorg Med Chem Lett 22: 3498-3502

  • DOI: https://doi.org/10.1016/j.bmcl.2012.03.083
  • Primary Citation of Related Structures:  
    4DIJ

  • PubMed Abstract: 

    Disrupting the interaction between the p53 tumor suppressor and its regulator MDM2 is a promising therapeutic strategy in anticancer drug research. In our search for non peptide inhibitors of this protein-protein interaction, we have devised a ligand design concept exploiting the central position of Val 93 in the p53 binding pocket of MDM2. The design of molecules based on this concept has allowed us to rapidly identify compounds having a 3-imidazolyl indole core structure as the first representatives of a new class of potent inhibitors of the p53-MDM2 interaction.


  • Organizational Affiliation

    Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland. [email protected]


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
E3 ubiquitin-protein ligase Mdm2
A, B
96Homo sapiensMutation(s): 1 
Gene Names: MDM2
EC: 6.3.2 (PDB Primary Data), 2.3.2.27 (UniProt)
UniProt & NIH Common Fund Data Resources
Find proteins for Q00987 (Homo sapiens)
Explore Q00987 
Go to UniProtKB:  Q00987
PHAROS:  Q00987
GTEx:  ENSG00000135679 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ00987
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
BLF
Query on BLF

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
6-chloro-3-[1-(4-chlorobenzyl)-4-phenyl-1H-imidazol-5-yl]-N-[2-(morpholin-4-yl)ethyl]-1H-indole-2-carboxamide
C31 H29 Cl2 N5 O2
IFORBTVIRBZFON-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
BLF PDBBind:  4DIJ IC50: 30 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.224 
  • R-Value Work: 0.194 
  • R-Value Observed: 0.195 
  • Space Group: P 43
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 38.234α = 90
b = 38.234β = 90
c = 175.151γ = 90
Software Package:
Software NamePurpose
RemDAqdata collection
MOLREPphasing
REFMACrefinement
HKL-2000data reduction
SCALEPACKdata scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2012-05-02 
  • Deposition Author(s): Kallen, J.

Revision History  (Full details and data files)

  • Version 1.0: 2012-05-02
    Type: Initial release
  • Version 1.1: 2012-05-23
    Changes: Database references
  • Version 1.2: 2017-11-15
    Changes: Refinement description
  • Version 1.3: 2024-02-28
    Changes: Data collection, Database references, Derived calculations
  • Version 1.4: 2024-04-03
    Changes: Refinement description