4KAO

FOCAL ADHESION KINASE CATALYTIC DOMAIN IN COMPLEX WITH 1-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-(4-pyridin-3- yl-phenyl)-urea


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.39 Å
  • R-Value Free: 0.216 
  • R-Value Work: 0.181 
  • R-Value Observed: 0.183 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Fragment-based discovery of focal adhesion kinase inhibitors.

Gradler, U.Bomke, J.Musil, D.Dresing, V.Lehmann, M.Holzemann, G.Greiner, H.Esdar, C.Krier, M.Heinrich, T.

(2013) Bioorg Med Chem Lett 23: 5401-5409

  • DOI: https://doi.org/10.1016/j.bmcl.2013.07.050
  • Primary Citation of Related Structures:  
    4K8A, 4K9Y, 4KAB, 4KAO

  • PubMed Abstract: 

    Chemically diverse fragment hits of focal adhesion kinase (FAK) were discovered by surface plasmon resonance (SPR) screening of our in-house fragment library. Site specific binding of the primary hits was confirmed in a competition setup using a high-affinity ATP-site inhibitor of FAK. Protein crystallography revealed the binding mode of 41 out of 48 selected fragment hits within the ATP-site. Structural comparison of the fragment binding modes with a DFG-out inhibitor of FAK initiated first synthetic follow-up optimization leading to improved binding affinity.


  • Organizational Affiliation

    Merck KGaA, Merck Serono Research, Darmstadt, Germany. ulrich.graedler@merckgroup.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Focal adhesion kinase 1
A, B
282Homo sapiensMutation(s): 1 
Gene Names: PTK2FAKFAK1
EC: 2.7.10.2
UniProt & NIH Common Fund Data Resources
Find proteins for Q05397 (Homo sapiens)
Explore Q05397 
Go to UniProtKB:  Q05397
PHAROS:  Q05397
GTEx:  ENSG00000169398 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ05397
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
KAO
Query on KAO

Download Ideal Coordinates CCD File 
C [auth A],
E [auth B]
1-[3-tert-butyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]-3-[4-(pyridin-3-yl)phenyl]urea
C26 H27 N5 O
JMQOIKOCLOMDPW-UHFFFAOYSA-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
KAO PDBBind:  4KAO Kd: 770 (nM) from 1 assay(s)
Binding MOAD:  4KAO Kd: 770 (nM) from 1 assay(s)
BindingDB:  4KAO Kd: 770 (nM) from 1 assay(s)
IC50: min: 7000, max: 1.00e+4 (nM) from 2 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.39 Å
  • R-Value Free: 0.216 
  • R-Value Work: 0.181 
  • R-Value Observed: 0.183 
  • Space Group: P 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 46.43α = 96.51
b = 52.29β = 103.12
c = 65.2γ = 89.44
Software Package:
Software NamePurpose
PHASERphasing
BUSTERrefinement
XDSdata reduction
XSCALEdata 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: 2013-09-11
    Type: Initial release
  • Version 1.1: 2013-10-09
    Changes: Database references