This old version of Proteopedia is provided for student assignments while the new version is undergoing repairs. Content and edits done in this old version of Proteopedia after March 1, 2026 will eventually be lost when it is retired in about June of 2026.
Apply for new accounts at the new Proteopedia. Your logins will work in both the old and new versions.
2ogv
From Proteopedia
(New page: 200px<br /> <applet load="2ogv" size="450" color="white" frame="true" align="right" spinBox="true" caption="2ogv, resolution 2.70Å" /> '''Crystal Structure o...) |
|||
| Line 1: | Line 1: | ||
| - | [[Image:2ogv.gif|left|200px]]<br /> | + | [[Image:2ogv.gif|left|200px]]<br /><applet load="2ogv" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="2ogv" size=" | + | |
caption="2ogv, resolution 2.70Å" /> | caption="2ogv, resolution 2.70Å" /> | ||
'''Crystal Structure of the Autoinhibited Human c-Fms Kinase Domain'''<br /> | '''Crystal Structure of the Autoinhibited Human c-Fms Kinase Domain'''<br /> | ||
| Line 6: | Line 5: | ||
==Overview== | ==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. | 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== | ||
| - | 2OGV is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Active as [http://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] Full crystallographic information is available from [http:// | + | 2OGV is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Active as [http://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2OGV OCA]. |
==Reference== | ==Reference== | ||
| Line 30: | Line 26: | ||
[[Category: receptor tyrosine kinase]] | [[Category: receptor tyrosine kinase]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 23 15:25:07 2008'' |
Revision as of 13:25, 23 January 2008
|
Crystal Structure of the Autoinhibited Human c-Fms Kinase Domain
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.
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 Wed Jan 23 15:25:07 2008
