2J2I

Crystal Structure of the humab PIM1 in complex with LY333531


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.200 
  • R-Value Work: 0.179 
  • R-Value Observed: 0.180 

Starting Model: experimental
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Ligand Structure Quality Assessment 


This is version 1.7 of the entry. See complete history


Literature

A systematic interaction map of validated kinase inhibitors with Ser/Thr kinases.

Fedorov, O.Marsden, B.Pogacic, V.Rellos, P.Muller, S.Bullock, A.N.Schwaller, J.Sundstrom, M.Knapp, S.

(2007) Proc Natl Acad Sci U S A 104: 20523-20528

  • DOI: https://doi.org/10.1073/pnas.0708800104
  • Primary Citation of Related Structures:  
    2J2I

  • PubMed Abstract: 

    Protein kinases play a pivotal role in cell signaling, and dysregulation of many kinases has been linked to disease development. A large number of kinase inhibitors are therefore currently under investigation in clinical trials, and so far seven inhibitors have been approved as anti-cancer drugs. In addition, kinase inhibitors are widely used as specific probes to study cell signaling, but systematic studies describing selectivity of these reagents across a panel of diverse kinases are largely lacking. Here we evaluated the specificity of 156 validated kinase inhibitors, including inhibitors used in clinical trials, against 60 human Ser/Thr kinases using a thermal stability shift assay. Our analysis revealed many unexpected cross-reactivities for inhibitors thought to be specific for certain targets. We also found that certain combinations of active-site residues in the ATP-binding site correlated with the detected ligand promiscuity and that some kinases are highly sensitive to inhibition using diverse chemotypes, suggesting them as preferred intervention points. Our results uncovered also inhibitor cross-reactivities that may lead to alternate clinical applications. For example, LY333'531, a PKCbeta inhibitor currently in phase III clinical trials, efficiently inhibited PIM1 kinase in our screen, a suggested target for treatment of leukemia. We determined the binding mode of this inhibitor by x-ray crystallography and in addition showed that LY333'531 induced cell death and significantly suppressed growth of leukemic cells from acute myeloid leukemia patients.


  • Organizational Affiliation

    Structural Genomics Consortium, Botnar Research Centre, University of Oxford, Oxford OX3 7LD, United Kingdom.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
PROTO-ONCOGENE SERINE/THREONINE-PROTEIN KINASE PIM-1A [auth B]312Homo sapiensMutation(s): 1 
EC: 2.7.11.1
UniProt & NIH Common Fund Data Resources
Find proteins for P11309 (Homo sapiens)
Explore P11309 
Go to UniProtKB:  P11309
PHAROS:  P11309
GTEx:  ENSG00000137193 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP11309
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
LY4
Query on LY4

Download Ideal Coordinates CCD File 
C [auth B](9R)-9-[(DIMETHYLAMINO)METHYL]-6,7,10,11-TETRAHYDRO-9H,18H-5,21:12,17-DIMETHENODIBENZO[E,K]PYRROLO[3,4-H][1,4,13]OXADIA ZACYCLOHEXADECINE-18,20-DIONE
C28 H28 N4 O3
ZCBUQCWBWNUWSU-SFHVURJKSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
B
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
Binding Affinity Annotations 
IDSourceBinding Affinity
LY4 BindingDB:  2J2I Kd: min: 50, max: 270 (nM) from 3 assay(s)
IC50: 200 (nM) from 1 assay(s)
PDBBind:  2J2I IC50: 200 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.200 
  • R-Value Work: 0.179 
  • R-Value Observed: 0.180 
  • Space Group: P 65
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 98.157α = 90
b = 98.157β = 90
c = 80.366γ = 120
Software Package:
Software NamePurpose
REFMACrefinement
DENZOdata reduction
SCALEPACKdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2007-02-13
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Advisory, Version format compliance
  • Version 1.2: 2018-01-24
    Changes: Structure summary
  • Version 1.3: 2018-02-28
    Changes: Database references, Source and taxonomy
  • Version 1.4: 2018-04-04
    Changes: Data collection
  • Version 1.5: 2019-03-06
    Changes: Data collection, Experimental preparation
  • Version 1.6: 2019-05-08
    Changes: Data collection, Experimental preparation
  • Version 1.7: 2023-12-13
    Changes: Data collection, Database references, Derived calculations, Other, Refinement description, Structure summary