3EN4

Targeted polypharmacology: crystal structure of the c-Src kinase domain in complex with PP121, a multitargeted kinase inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.55 Å
  • R-Value Free: 0.255 
  • R-Value Work: 0.198 
  • R-Value Observed: 0.201 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Targeted polypharmacology: discovery of dual inhibitors of tyrosine and phosphoinositide kinases.

Apsel, B.Blair, J.A.Gonzalez, B.Nazif, T.M.Feldman, M.E.Aizenstein, B.Hoffman, R.Williams, R.L.Shokat, K.M.Knight, Z.A.

(2008) Nat Chem Biol 4: 691-699

  • DOI: https://doi.org/10.1038/nchembio.117
  • Primary Citation of Related Structures:  
    2V4L, 3EN4, 3EN5, 3EN6, 3EN7, 3ENE

  • PubMed Abstract: 

    The clinical success of multitargeted kinase inhibitors has stimulated efforts to identify promiscuous drugs with optimal selectivity profiles. It remains unclear to what extent such drugs can be rationally designed, particularly for combinations of targets that are structurally divergent. Here we report the systematic discovery of molecules that potently inhibit both tyrosine kinases and phosphatidylinositol-3-OH kinases, two protein families that are among the most intensely pursued cancer drug targets. Through iterative chemical synthesis, X-ray crystallography and kinome-level biochemical profiling, we identified compounds that inhibit a spectrum of new target combinations in these two families. Crystal structures revealed that the dual selectivity of these molecules is controlled by a hydrophobic pocket conserved in both enzyme classes and accessible through a rotatable bond in the drug skeleton. We show that one compound, PP121, blocks the proliferation of tumor cells by direct inhibition of oncogenic tyrosine kinases and phosphatidylinositol-3-OH kinases. These molecules demonstrate the feasibility of accessing a chemical space that intersects two families of oncogenes.


  • Organizational Affiliation

    Program in Chemistry and Chemical Biology, University of California, San Francisco, 600 16th Street, San Francisco, California 94158, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Proto-oncogene tyrosine-protein kinase Src
A, B
286Gallus gallusMutation(s): 0 
Gene Names: SRC
EC: 2.7.10.2
UniProt
Find proteins for P00523 (Gallus gallus)
Explore P00523 
Go to UniProtKB:  P00523
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP00523
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
KS1
Query on KS1

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
1-cyclopentyl-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
C17 H17 N7
NVRXTLZYXZNATH-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.55 Å
  • R-Value Free: 0.255 
  • R-Value Work: 0.198 
  • R-Value Observed: 0.201 
  • Space Group: P 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 42.37α = 100.63
b = 63.143β = 88.68
c = 73.938γ = 90.4
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
PHASERphasing
REFMACrefinement
PDB_EXTRACTdata extraction
HKL-2000data collection
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2008-10-14
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Advisory, Version format compliance
  • Version 1.2: 2017-10-25
    Changes: Refinement description
  • Version 1.3: 2023-09-06
    Changes: Data collection, Database references, Derived calculations, Refinement description