The 2.7 A crystal structure of the autoinhibited human c-Fms kinase domain.
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.
Walter
Mark
M
Protein Crystallography Unit, Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia.
Lucet
Isabelle S
IS
Patel
Onisha
O
Broughton
Sophie E
SE
Bamert
Rebecca
R
Williams
Neal K
NK
Fantino
Emmanuelle
E
Wilks
Andrew F
AF
Rossjohn
Jamie
J
D000595:Amino Acid Sequence; D001549:Benzamides; D018360:Crystallography, X-Ray; D006801:Humans; D000068877:Imatinib Mesylate; D066298:In Vitro Techniques; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D000090063:Proto-Oncogene Mas; D011743:Pyrimidines / Q000494:pharmacology; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics; D017386:Sequence Homology, Amino Acid
D001549:Benzamides; C000715470:MAS1 protein, human; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D000090063:Proto-Oncogene Mas; D011743:Pyrimidines; D011994:Recombinant Proteins; D000068877:Imatinib Mesylate; D016186:Receptor, Macrophage Colony-Stimulating Factor