2N14

Mdmx-295


Experimental Data Snapshot

  • Method: SOLUTION NMR
  • Conformers Calculated: 100 
  • Conformers Submitted: 20 
  • Selection Criteria: target function 

wwPDB Validation   3D Report Full Report


This is version 1.1 of the entry. See complete history


Literature

Monitoring Ligand-Induced Protein Ordering in Drug Discovery.

Grace, C.R.Ban, D.Min, J.Mayasundari, A.Min, L.Finch, K.E.Griffiths, L.Bharatham, N.Bashford, D.Kiplin Guy, R.Dyer, M.A.Kriwacki, R.W.

(2016) J Mol Biol 428: 1290-1303

  • DOI: https://doi.org/10.1016/j.jmb.2016.01.016
  • Primary Citation of Related Structures:  
    2MWY, 2N06, 2N0U, 2N0W, 2N14

  • PubMed Abstract: 

    While the gene for p53 is mutated in many human cancers causing loss of function, many others maintain a wild-type gene but exhibit reduced p53 tumor suppressor activity through overexpression of the negative regulators, Mdm2 and/or MdmX. For the latter mechanism of loss of function, the activity of endogenous p53 can be restored through inhibition of Mdm2 or MdmX with small molecules. We previously reported a series of compounds based upon the Nutlin-3 chemical scaffold that bind to both MdmX and Mdm2 [Vara, B. A. et al. (2014) Organocatalytic, diastereo- and enantioselective synthesis of nonsymmetric cis-stilbene diamines: A platform for the preparation of single-enantiomer cis-imidazolines for protein-protein inhibition. J. Org. Chem. 79, 6913-6938]. Here we present the first solution structures based on data from NMR spectroscopy for MdmX in complex with four of these compounds and compare them with the MdmX:p53 complex. A p53-derived peptide binds with high affinity (Kd value of 150nM) and causes the formation of an extensive network of hydrogen bonds within MdmX; this constitutes the induction of order within MdmX through ligand binding. In contrast, the compounds bind more weakly (Kd values from 600nM to 12μM) and induce an incomplete hydrogen bond network within MdmX. Despite relatively weak binding, the four compounds activated p53 and induced p21(Cip1) expression in retinoblastoma cell lines that overexpress MdmX, suggesting that they specifically target MdmX and/or Mdm2. Our results document structure-activity relationships for lead-like small molecules targeting MdmX and suggest a strategy for their further optimization in the future by using NMR spectroscopy to monitor small-molecule-induced protein order as manifested through hydrogen bond formation.


  • Organizational Affiliation

    Department of Structural Biology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Protein Mdm489Homo sapiensMutation(s): 0 
Gene Names: MDM4MDMX
UniProt & NIH Common Fund Data Resources
Find proteins for O15151 (Homo sapiens)
Explore O15151 
Go to UniProtKB:  O15151
PHAROS:  O15151
GTEx:  ENSG00000198625 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO15151
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
49H
Query on 49H

Download Ideal Coordinates CCD File 
B [auth A]4-({(4S,5R)-4-(3-chlorophenyl)-5-(4-chlorophenyl)-2-[4-methoxy-2-(propan-2-yloxy)phenyl]-4,5-dihydro-1H-imidazol-1-yl}carbonyl)piperazin-2-one
C30 H30 Cl2 N4 O4
WCJXJRYBDXHZRN-WUFINQPMSA-N
Experimental Data & Validation

Experimental Data

  • Method: SOLUTION NMR
  • Conformers Calculated: 100 
  • Conformers Submitted: 20 
  • Selection Criteria: target function 

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2016-01-27
    Type: Initial release
  • Version 1.1: 2016-05-04
    Changes: Database references