2I0Y

cFMS tyrosine kinase (FGF KID) in complex with an arylamide inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.263 
  • R-Value Work: 0.238 
  • R-Value Observed: 0.246 

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Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Crystal structure of the tyrosine kinase domain of colony-stimulating factor-1 receptor (cFMS) in complex with two inhibitors.

Schubert, C.Schalk-Hihi, C.Struble, G.T.Ma, H.C.Petrounia, I.P.Brandt, B.Deckman, I.C.Patch, R.J.Player, M.R.Spurlino, J.C.Springer, B.A.

(2007) J Biol Chem 282: 4094-4101

  • DOI: https://doi.org/10.1074/jbc.M608183200
  • Primary Citation of Related Structures:  
    2I0V, 2I0Y, 2I1M

  • PubMed Abstract: 

    The cFMS proto-oncogene encodes for the colony-stimulating factor-1 receptor, a receptor-tyrosine kinase responsible for the differentiation and maturation of certain macrophages. Upon binding its ligand colony-stimulating factor-1 cFMS autophosphorylates, dimerizes, and induces phosphorylation of downstream targets. We report the novel crystal structure of unphosphorylated cFMS in complex with two members of different classes of drug-like protein kinase inhibitors. cFMS exhibits a typical bi-lobal kinase fold, and its activation loop and DFG motif are found to be in the canonical inactive conformation. Both ATP competitive inhibitors are bound in the active site and demonstrate a binding mode similar to that of STI-571 bound to cABL. The DFG motif is prevented from switching into the catalytically competent conformation through interactions with the inhibitors. Activation of cFMS is also inhibited by the juxtamembrane domain, which interacts with residues of the active site and prevents formation of the activated kinase. Together the structures of cFMS provide further insight into the autoinhibition of receptor-tyrosine kinases via their respective juxtamembrane domains; additionally the binding mode of two novel classes of kinase inhibitors will guide the design of novel molecules targeting macrophage-related diseases.


  • Organizational Affiliation

    Structural Biology, Johnson & Johnson Pharmaceuticals Research and Development, LLC, Exton, Pennsylvania 19341, USA. cschuber@prdus.jnj.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
cFMS Tyrosine Kinase335Homo sapiensMutation(s): 0 
EC: 2.7.10.1
UniProt & NIH Common Fund Data Resources
Find proteins for P07333 (Homo sapiens)
Explore P07333 
Go to UniProtKB:  P07333
PHAROS:  P07333
GTEx:  ENSG00000182578 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP07333
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
5CN
Query on 5CN

Download Ideal Coordinates CCD File 
B [auth A]5-CYANO-FURAN-2-CARBOXYLIC ACID [5-HYDROXYMETHYL-2-(4-METHYL-PIPERIDIN-1-YL)-PHENYL]-AMIDE
C19 H21 N3 O3
NNPCFFIJVKYGHR-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
5CN PDBBind:  2I0Y IC50: 24 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.263 
  • R-Value Work: 0.238 
  • R-Value Observed: 0.246 
  • Space Group: H 3
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 81.07α = 90
b = 81.07β = 90
c = 144.67γ = 120
Software Package:
Software NamePurpose
CNXrefinement
ADSCdata collection
HKL-2000data reduction
SCALEPACKdata scaling
CNXphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2006-11-28
    Type: Initial release
  • Version 1.1: 2007-10-03
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2017-08-23
    Changes: Source and taxonomy
  • Version 1.4: 2024-02-21
    Changes: Data collection, Database references, Derived calculations