4ZYC

Discovery of dihydroisoquinolinone derivatives as novel inhibitors of the p53-MDM2 interaction with a distinct binding mode: Hdm2 (MDM2) complexed with cpd5


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.259 
  • R-Value Work: 0.220 
  • R-Value Observed: 0.222 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Discovery of dihydroisoquinolinone derivatives as novel inhibitors of the p53-MDM2 interaction with a distinct binding mode.

Gessier, F.Kallen, J.Jacoby, E.Chene, P.Stachyra-Valat, T.Ruetz, S.Jeay, S.Holzer, P.Masuya, K.Furet, P.

(2015) Bioorg Med Chem Lett 25: 3621-3625

  • DOI: https://doi.org/10.1016/j.bmcl.2015.06.058
  • Primary Citation of Related Structures:  
    4ZYC

  • PubMed Abstract: 

    Blocking the interaction between the p53 tumor suppressor and its regulatory protein MDM2 is a promising therapeutic concept under current investigation in oncology drug research. We report here the discovery of the first representatives of a new class of small molecule inhibitors of this protein-protein interaction: the dihydroisoquinolinones. Starting from an initial hit identified by virtual screening, a derivatization program has resulted in compound 11, a low nanomolar inhibitor of the p53-MDM2 interaction showing significant cellular activity. Initially based on a binding mode hypothesis, this effort was then guided by a X-ray co-crystal structure of MDM2 in complex with one of the synthesized analogs. The X-ray structure revealed an unprecedented binding mode for p53-MDM2 inhibitors.


  • Organizational Affiliation

    Novartis Institutes for BioMedical Research, WKL-136.P.12, CH-4002 Basel, Switzerland.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
E3 ubiquitin-protein ligase Mdm2
A, B, C
96Homo sapiensMutation(s): 1 
Gene Names: MDM2
EC: 6.3.2
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
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  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
4SS Binding MOAD:  4ZYC IC50: 380 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.259 
  • R-Value Work: 0.220 
  • R-Value Observed: 0.222 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 39.02α = 90
b = 49.78β = 92.77
c = 75.287γ = 90
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
MOLREPphasing
REFMACrefinement
PDB_EXTRACTdata extraction

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2015-07-22 
  • Deposition Author(s): Kallen, J.

Revision History  (Full details and data files)

  • Version 1.0: 2015-07-22
    Type: Initial release
  • Version 1.1: 2015-08-12
    Changes: Database references
  • Version 1.2: 2017-11-29
    Changes: Database references
  • Version 1.3: 2024-01-10
    Changes: Data collection, Database references, Refinement description