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

Walter, Mark, Lucet, Isabelle S., Patel, Onisha, Broughton, Sophie E., Bamert, Rebecca, Williams, Neal K., Fantino, Emmanuelle, Wilks, Andrew F. and Rossjohn, Jamie (2007) The 2.7 angstrom crystal structure of the autoinhibited human c-Fms kinase domain. Journal of Molecular Biology, 367 3: 839-847. doi:10.1016/j.jmb.2007.01.036

Author Walter, Mark
Lucet, Isabelle S.
Patel, Onisha
Broughton, Sophie E.
Bamert, Rebecca
Williams, Neal K.
Fantino, Emmanuelle
Wilks, Andrew F.
Rossjohn, Jamie
Title The 2.7 angstrom crystal structure of the autoinhibited human c-Fms kinase domain
Journal name Journal of Molecular Biology   Check publisher's open access policy
ISSN 0022-2836
Publication date 2007-03
Sub-type Article (original research)
DOI 10.1016/j.jmb.2007.01.036
Volume 367
Issue 3
Start page 839
End page 847
Total pages 9
Place of publication London, United Kingdom
Publisher Academic Press
Language eng
Formatted 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 Å 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.
Keyword Macrophage colony stimulating factor receptor
Receptor tyrosine kinase
Autoinhibitory mechanism
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Faculty of Health and Behavioural Sciences -- Publications
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