4HBM

Ordering of the N Terminus of Human MDM2 by Small Molecule Inhibitors


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.240 
  • R-Value Work: 0.220 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Ordering of the N-terminus of human MDM2 by small molecule inhibitors.

Michelsen, K.Jordan, J.B.Lewis, J.Long, A.M.Yang, E.Rew, Y.Zhou, J.Yakowec, P.Schnier, P.D.Huang, X.Poppe, L.

(2012) J Am Chem Soc 134: 17059-17067

  • DOI: https://doi.org/10.1021/ja305839b
  • Primary Citation of Related Structures:  
    2LZG, 4HBM

  • PubMed Abstract: 

    Restoration of p53 function through the disruption of the MDM2-p53 protein complex is a promising strategy for the treatment of various types of cancer. Here, we present kinetic, thermodynamic, and structural rationale for the remarkable potency of a new class of MDM2 inhibitors, the piperidinones. While these compounds bind to the same site as previously reported for small molecule inhibitors, such as the Nutlins, data presented here demonstrate that the piperidinones also engage the N-terminal region (residues 10-16) of human MDM2, in particular, Val14 and Thr16. This portion of MDM2 is unstructured in both the apo form of the protein and in MDM2 complexes with p53 or Nutlin, but adopts a novel β-strand structure when complexed with the piperidinones. The ordering of the N-terminus upon binding of the piperidinones extends the current model of MDM2-p53 interaction and provides a new route to rational design of superior inhibitors.


  • Organizational Affiliation

    Molecular Structure & Characterization, Amgen, Inc., Thousand Oaks, California 91320, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
E3 ubiquitin-protein ligase Mdm2
A, B, C, D, E
A, B, C, D, E, F, G, H
120Homo sapiensMutation(s): 0 
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
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
0Y7 PDBBind:  4HBM Kd: 12 (nM) from 1 assay(s)
Binding MOAD:  4HBM Kd: 12 (nM) from 1 assay(s)
BindingDB:  4HBM IC50: 50 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.240 
  • R-Value Work: 0.220 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 185.35α = 90
b = 73.95β = 121.6
c = 123.09γ = 90
Software Package:
Software NamePurpose
HKL-2000data collection
CNSrefinement
DENZOdata reduction
SCALEPACKdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2012-10-17 
  • Deposition Author(s): Huang, X.

Revision History  (Full details and data files)

  • Version 1.0: 2012-10-17
    Type: Initial release
  • Version 1.1: 2013-01-02
    Changes: Database references
  • Version 1.2: 2024-02-28
    Changes: Data collection, Database references, Derived calculations