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PDBsum entry 2i0y

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Transferase PDB id
2i0y
Jmol
Contents
Protein chain
289 a.a. *
Ligands
5CN
Waters ×101
* Residue conservation analysis
PDB id:
2i0y
Name: Transferase
Title: Cfms tyrosine kinase (fgf kid) in complex with an arylamide inhibitor
Structure: Cfms tyrosine kinase. Chain: a. Fragment: kinase domain. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108
Resolution:
1.90Å     R-factor:   0.246     R-free:   0.263
Authors: C.Schubert,C.Schalk-Hihi
Key ref:
C.Schubert et al. (2007). Crystal structure of the tyrosine kinase domain of colony-stimulating factor-1 receptor (cFMS) in complex with two inhibitors. J Biol Chem, 282, 4094-4101. PubMed id: 17132624 DOI: 10.1074/jbc.M608183200
Date:
11-Aug-06     Release date:   28-Nov-06    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P07333  (CSF1R_HUMAN) -  Macrophage colony-stimulating factor 1 receptor
Seq:
Struc:
 
Seq:
Struc:
972 a.a.
289 a.a.*
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 3 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: E.C.2.7.10.1  - Receptor protein-tyrosine kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate
ATP
+ [protein]-L-tyrosine
= ADP
+ [protein]-L-tyrosine phosphate
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     membrane   1 term 
  Biological process     transmembrane receptor protein tyrosine kinase signaling pathway   2 terms 
  Biochemical function     transferase activity, transferring phosphorus-containing groups     5 terms  

 

 
    reference    
 
 
DOI no: 10.1074/jbc.M608183200 J Biol Chem 282:4094-4101 (2007)
PubMed id: 17132624  
 
 
Crystal structure of the tyrosine kinase domain of colony-stimulating factor-1 receptor (cFMS) in complex with two inhibitors.
C.Schubert, C.Schalk-Hihi, G.T.Struble, H.C.Ma, I.P.Petrounia, B.Brandt, I.C.Deckman, R.J.Patch, M.R.Player, J.C.Spurlino, B.A.Springer.
 
  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.
 
  Selected figure(s)  
 
Figure 1.
FIGURE 1. A, overview of the cFMS structure (TIE2-KID) with bound inhibitor 1. Structural elements are color-coded: blue, (N)ucleotide binding loop (P-loop); red, activation loop; green, catalytic loop; salmon, hinge region; cyan, KID; yellow, JM domain. B, structures of the inhibitors used in this study, 1 arylamide series inhibitor, 2 quinolone series inhibitor.
Figure 3.
FIGURE 3. Role of the JM domain in stabilizing the inactive form of cFMS. cFMS is shown in a white surface representation, the activation loop (red) and the JM domain (yellow) were excluded from the surface calculation and are represented as red and yellow schemes, respectively. Trp^550 is also represented as a surface. The activation loop of activated cKIT (PDB-ID 1PKG), superimposed onto cFMS, is shown in green. In its autoinhibited state, the JM domain of cFMS inserts itself into the active site and prevents the activation loop from switching into an active conformation.
 
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2007, 282, 4094-4101) copyright 2007.  
  Figures were selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
23076159 K.Verstraete, and S.N.Savvides (2012).
Extracellular assembly and activation principles of oncogenic class III receptor tyrosine kinases.
  Nat Rev Cancer, 12, 753-766.  
21095574 L.M.Wodicka, P.Ciceri, M.I.Davis, J.P.Hunt, M.Floyd, S.Salerno, X.H.Hua, J.M.Ford, R.C.Armstrong, P.P.Zarrinkar, and D.K.Treiber (2010).
Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry.
  Chem Biol, 17, 1241-1249.  
20336692 M.Rabiller, M.Getlik, S.Klüter, A.Richters, S.Tückmantel, J.R.Simard, and D.Rauh (2010).
Proteus in the world of proteins: conformational changes in protein kinases.
  Arch Pharm (Weinheim), 343, 193-206.  
19151753 S.Bhattacharyya, W.Ishida, M.Wu, M.Wilkes, Y.Mori, M.Hinchcliff, E.Leof, and J.Varga (2009).
A non-Smad mechanism of fibroblast activation by transforming growth factor-beta via c-Abl and Egr-1: selective modulation by imatinib mesylate.
  Oncogene, 28, 1285-1297.  
17851554 N.Brownlow, A.E.Russell, H.Saravanapavan, M.Wiesmann, J.M.Murray, P.W.Manley, and N.J.Dibb (2008).
Comparison of nilotinib and imatinib inhibition of FMS receptor signaling, macrophage production and osteoclastogenesis.
  Leukemia, 22, 649-652.  
17965187 M.Ikuta, M.Kornienko, N.Byrne, J.C.Reid, S.Mizuarai, H.Kotani, and S.K.Munshi (2007).
Crystal structures of the N-terminal kinase domain of human RSK1 bound to three different ligands: Implications for the design of RSK1 specific inhibitors.
  Protein Sci, 16, 2626-2635.
PDB codes: 2z7q 2z7r 2z7s
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