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...) |
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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 /> | ||
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==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. | ||
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| - | ==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== | ||
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[[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
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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
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