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| {{STRUCTURE_2ogv| PDB=2ogv | SCENE= }} | | {{STRUCTURE_2ogv| PDB=2ogv | SCENE= }} |
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| '''Crystal Structure of the Autoinhibited Human c-Fms Kinase Domain'''
| | ===Crystal Structure of the Autoinhibited Human c-Fms Kinase Domain=== |
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| ==Overview==
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| 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.
| | The line below this paragraph, {{ABSTRACT_PUBMED_17292918}}, adds the Publication Abstract to the page |
| | (as it appears on PubMed at http://www.pubmed.gov), where 17292918 is the PubMed ID number. |
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| | {{ABSTRACT_PUBMED_17292918}} |
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| ==About this Structure== | | ==About this Structure== |
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| [[Category: Macrophage colony stimulating factor receptor]] | | [[Category: Macrophage colony stimulating factor receptor]] |
| [[Category: Receptor tyrosine kinase]] | | [[Category: Receptor tyrosine kinase]] |
| ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 10:53:22 2008'' | | |
| | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 29 03:37:06 2008'' |
