4ERE

crystal structure of MDM2 (17-111) in complex with compound 23


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.270 
  • R-Value Work: 0.250 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Structure-based design of novel inhibitors of the MDM2-p53 interaction.

Rew, Y.Sun, D.Gonzalez-Lopez De Turiso, F.Bartberger, M.D.Beck, H.P.Canon, J.Chen, A.Chow, D.Deignan, J.Fox, B.M.Gustin, D.Huang, X.Jiang, M.Jiao, X.Jin, L.Kayser, F.Kopecky, D.J.Li, Y.Lo, M.C.Long, A.M.Michelsen, K.Oliner, J.D.Osgood, T.Ragains, M.Saiki, A.Y.Schneider, S.Toteva, M.Yakowec, P.Yan, X.Ye, Q.Yu, D.Zhao, X.Zhou, J.Medina, J.C.Olson, S.H.

(2012) J Med Chem 55: 4936-4954

  • DOI: https://doi.org/10.1021/jm300354j
  • Primary Citation of Related Structures:  
    4ERE, 4ERF

  • PubMed Abstract: 

    Structure-based rational design led to the discovery of novel inhibitors of the MDM2-p53 protein-protein interaction. The affinity of these compounds for MDM2 was improved through conformational control of both the piperidinone ring and the appended N-alkyl substituent. Optimization afforded 29 (AM-8553), a potent and selective MDM2 inhibitor with excellent pharmacokinetic properties and in vivo efficacy.


  • Organizational Affiliation

    Department of Therapeutic Discovery, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, California 94080, United States.


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): 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
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
0R2
Query on 0R2

Download Ideal Coordinates CCD File 
C [auth A],
E [auth B]
[(3R,5R,6S)-1-[(2S)-1-tert-butoxy-1-oxobutan-2-yl]-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-3-yl]acetic acid
C27 H31 Cl2 N O5
ZEMLYWMOSZRCQL-UWSZBUKDSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
D [auth A]SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
Binding Affinity Annotations 
IDSourceBinding Affinity
0R2 BindingDB:  4ERE IC50: min: 4, max: 40 (nM) from 2 assay(s)
PDBBind:  4ERE IC50: 4.2 (nM) from 1 assay(s)
Binding MOAD:  4ERE IC50: 4.2 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.270 
  • R-Value Work: 0.250 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 43.15α = 90
b = 60.24β = 90
c = 68.09γ = 90
Software Package:
Software NamePurpose
CrystalCleardata collection
AMoREphasing
CNSrefinement
DENZOdata reduction
SCALEPACKdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2012-05-23 
  • Deposition Author(s): Huang, X.

Revision History  (Full details and data files)

  • Version 1.0: 2012-05-23
    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