2ogv
From Proteopedia
| Line 4: | Line 4: | ||
==Overview== | ==Overview== | ||
| - | c-Fms, a member of the Platelet-derived Growth Factor (PDGF) receptor | + | 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. |
| + | |||
| + | ==Disease== | ||
| + | Known diseases associated with this structure: Myeloid malignancy, predisposition to OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=164770 164770]] | ||
==About this Structure== | ==About this Structure== | ||
| Line 15: | Line 18: | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Bamert, R.]] | [[Category: Bamert, R.]] | ||
| - | [[Category: Broughton, S | + | [[Category: Broughton, S E.]] |
[[Category: Fantino, E.]] | [[Category: Fantino, E.]] | ||
| - | [[Category: Lucet, I | + | [[Category: Lucet, I S.]] |
[[Category: Patel, O.]] | [[Category: Patel, O.]] | ||
[[Category: Rossjohn, J.]] | [[Category: Rossjohn, J.]] | ||
[[Category: Walter, M.]] | [[Category: Walter, M.]] | ||
| - | [[Category: Wilks, A | + | [[Category: Wilks, A F.]] |
| - | [[Category: Williams, N | + | [[Category: Williams, N K.]] |
[[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 | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 18:18:19 2008'' |
Revision as of 16:18, 21 February 2008
|
Crystal Structure of the Autoinhibited Human c-Fms Kinase Domain
Contents |
Overview
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.
Disease
Known diseases associated with this structure: Myeloid malignancy, predisposition to OMIM:[164770]
About this Structure
2OGV is a Single protein structure of sequence from Homo sapiens. Active as Receptor protein-tyrosine kinase, with EC number 2.7.10.1 Full crystallographic information is available from OCA.
Reference
The 2.7 A crystal structure of the autoinhibited human c-Fms kinase domain., Walter M, Lucet IS, Patel O, Broughton SE, Bamert R, Williams NK, Fantino E, Wilks AF, Rossjohn J, J Mol Biol. 2007 Mar 30;367(3):839-47. Epub 2007 Jan 20. PMID:17292918
Page seeded by OCA on Thu Feb 21 18:18:19 2008
