spacer
spacer

PDBsum entry 2ogv

Go to PDB code: 
protein links
Transferase PDB id
2ogv
Jmol
Contents
Protein chain
317 a.a. *
Waters ×91
* Residue conservation analysis
PDB id:
2ogv
Name: Transferase
Title: Crystal structure of the autoinhibited human c-fms kinase domain
Structure: Macrophage colony-stimulating factor 1 receptor precursor. Chain: a. Fragment: kinase domain: residues 543-918. Synonym: csf-1-r, fms proto-oncogene, c-fms, cd115 antigen. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: csf1r, fms. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.
Resolution:
2.70Å     R-factor:   0.210     R-free:   0.279
Authors: M.Walter,I.S.Lucet,O.Patel,S.E.Broughton,R.Bamert, N.K.Williams,E.Fantino,A.F.Wilks,J.Rossjohn
Key ref:
M.Walter et al. (2007). The 2.7 A crystal structure of the autoinhibited human c-Fms kinase domain. J Mol Biol, 367, 839-847. PubMed id: 17292918 DOI: 10.1016/j.jmb.2007.01.036
Date:
09-Jan-07     Release date:   06-Feb-07    
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.
317 a.a.
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain

 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: 10.1016/j.jmb.2007.01.036 J Mol Biol 367:839-847 (2007)
PubMed id: 17292918  
 
 
The 2.7 A crystal structure of the autoinhibited human c-Fms kinase domain.
M.Walter, I.S.Lucet, O.Patel, S.E.Broughton, R.Bamert, N.K.Williams, E.Fantino, A.F.Wilks, J.Rossjohn.
 
  ABSTRACT  
 
c-Fms, a member of the Platelet-derived Growth Factor (PDGF) receptor family of receptor tyrosine kinases (RTKs), is the receptor for macrophage colony stimulating factor (CSF-1) that regulates proliferation, differentiation and survival of cells of the mononuclear phagocyte lineage. Abnormal expression of c-fms proto-oncogene is associated with a significant number of human pathologies, including a variety of cancers and rheumatoid arthritis. Accordingly, c-Fms represents an attractive therapeutic target. To further understand the regulation of c-Fms, we determined the 2.7 A resolution crystal structure of the cytosolic domain of c-Fms that comprised the kinase domain and the juxtamembrane domain. The structure reveals the crucial inhibitory role of the juxtamembrane domain (JM) that binds to a hydrophobic site immediately adjacent to the ATP binding pocket. This interaction prevents the activation loop from adopting an active conformation thereby locking the c-Fms kinase into an autoinhibited state. As observed for other members of the PDGF receptor family, namely c-Kit and Flt3, three JM-derived tyrosine residues primarily drive the mechanism for autoinhibition in c-Fms, therefore defining a common autoinhibitory mechanism within this family. Moreover the structure provides an understanding of c-Fms inhibition by Gleevec as well as providing a platform for the development of more selective inhibitors that target the inactive conformation of c-Fms kinase.
 
  Selected figure(s)  
 
Figure 1.
Figure 3.
Figure 3. c-Fms juxtamembrane hydrogen-bonding interactions. (a) c-Fms JM domain with the JM-B (cyan), JM-S (magenta) and JM-Z (yellow), with the position of JM tyrosine residues: Tyr546, Tyr556, Tyr561 and Tyr571, as well as Asp565, are shown. (b) JM-B residue Tyr546 interaction with αC helix residues; Glu633 and Glu626 (magenta). (c) JM-B residues Arg549, Lys551 and Ile553 interacting with catalytic loop residues (magenta). JM-B Trp550 is also shown. (d) JM-S residues Leu569 and Tyr571interactions with αC helix residue Lys635 (magenta) and kinase domain residue Glu576 (light blue), respectively.
 
  The above figures are reprinted by permission from Elsevier: J Mol Biol (2007, 367, 839-847) copyright 2007.  
  Figures were selected by an automated process.  

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.  
21359601 P.M.Chan (2011).
Differential signaling of Flt3 activating mutations in acute myeloid leukemia: a working model.
  Protein Cell, 2, 108-115.  
19950162 K.Skobridis, M.Kinigopoulou, V.Theodorou, E.Giannousi, A.Russell, R.Chauhan, R.Sala, N.Brownlow, S.Kiriakidis, J.Domin, A.G.Tzakos, and N.J.Dibb (2010).
Novel imatinib derivatives with altered specificity between Bcr-Abl and FMS, KIT, and PDGF receptors.
  ChemMedChem, 5, 130-139.  
18971950 A.Chase, B.Schultheis, S.Kreil, J.Baxter, C.Hidalgo-Curtis, A.Jones, L.Zhang, F.H.Grand, J.V.Melo, and N.C.Cross (2009).
Imatinib sensitivity as a consequence of a CSF1R-Y571D mutation and CSF1/CSF1R signaling abnormalities in the cell line GDM1.
  Leukemia, 23, 358-364.  
19658168 E.Stuttfeld, and K.Ballmer-Hofer (2009).
Structure and function of VEGF receptors.
  IUBMB Life, 61, 915-922.  
18784745 N.Brownlow, C.Mol, C.Hayford, S.Ghaem-Maghami, and N.J.Dibb (2009).
Dasatinib is a potent inhibitor of tumour-associated macrophages, osteoclasts and the FMS receptor.
  Leukemia, 23, 590-594.  
19210352 S.Salemi, S.Yousefi, D.Simon, I.Schmid, L.Moretti, L.Scapozza, and H.U.Simon (2009).
A novel FIP1L1-PDGFRA mutant destabilizing the inactive conformation of the kinase domain in chronic eosinophilic leukemia/hypereosinophilic syndrome.
  Allergy, 64, 913-918.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time.