The 2.7 A crystal structure of the autoinhibited human c-Fms kinase domain

J Mol Biol. 2007 Mar 30;367(3):839-47. doi: 10.1016/j.jmb.2007.01.036. Epub 2007 Jan 20.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Benzamides
  • Crystallography, X-Ray
  • Humans
  • Imatinib Mesylate
  • In Vitro Techniques
  • Models, Molecular
  • Molecular Sequence Data
  • Piperazines / pharmacology
  • Protein Kinase Inhibitors / pharmacology
  • Protein Structure, Tertiary
  • Proto-Oncogene Mas
  • Pyrimidines / pharmacology
  • Receptor, Macrophage Colony-Stimulating Factor / antagonists & inhibitors*
  • Receptor, Macrophage Colony-Stimulating Factor / chemistry*
  • Receptor, Macrophage Colony-Stimulating Factor / genetics
  • Recombinant Proteins / antagonists & inhibitors
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Sequence Homology, Amino Acid


  • Benzamides
  • MAS1 protein, human
  • Piperazines
  • Protein Kinase Inhibitors
  • Proto-Oncogene Mas
  • Pyrimidines
  • Recombinant Proteins
  • Imatinib Mesylate
  • Receptor, Macrophage Colony-Stimulating Factor

Associated data

  • PDB/2OGV