2g15: Difference between revisions
New page: left|200px<br /><applet load="2g15" size="450" color="white" frame="true" align="right" spinBox="true" caption="2g15, resolution 2.15Å" /> '''Structural Character... |
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[[Image:2g15.gif|left|200px]]<br /><applet load="2g15" size=" | [[Image:2g15.gif|left|200px]]<br /><applet load="2g15" size="350" color="white" frame="true" align="right" spinBox="true" | ||
caption="2g15, resolution 2.15Å" /> | caption="2g15, resolution 2.15Å" /> | ||
'''Structural Characterization of autoinhibited c-Met kinase'''<br /> | '''Structural Characterization of autoinhibited c-Met kinase'''<br /> | ||
==Overview== | ==Overview== | ||
Protein kinases are a large family of cell signaling mediators undergoing | Protein kinases are a large family of cell signaling mediators undergoing intensive research to identify inhibitors or modulators useful for medicine. As one strategy, small-molecule compounds that bind the active site with high affinity can be used to inhibit the enzyme activity. X-ray crystallography is a powerful method to reveal the structures of the kinase active sites, and thus aid in the design of high-affinity, selective inhibitors. However, a limitation still exists in the ability to produce purified kinases in amounts sufficient for crystallography. Furthermore, kinases exist in different conformation states as part of their normal regulation, and the ability to prepare crystals of kinases in these various states also remains a limitation. In this study, the c-Abl, c-Src, and c-Met kinases are produced in high yields in Escherichia coli by using a bicistronic vector encoding the PTP1B tyrosine phosphatase. A 100-fold lower dose of the inhibitor, Imatinib, was observed to inhibit the unphosphorylated form of c-Abl kinase prepared by using this vector, compared to the phosphorylated form produced without PTP1B, consistent with the known selectivity of this inhibitor for the unactivated conformation of the enzyme. Unphosphorylated c-Met kinase produced with this vector was used to obtain the crystal structure, at 2.15-A resolution, of the autoinhibited form of the kinase domain, revealing an intricate network of interactions involving c-Met residues documented previously to cause dysregulation when mutated in several cancers. | ||
==About this Structure== | ==About this Structure== | ||
2G15 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http:// | 2G15 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2G15 OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Krupka, H | [[Category: Krupka, H I.]] | ||
[[Category: Kumar, A.]] | [[Category: Kumar, A.]] | ||
[[Category: Luu, C.]] | [[Category: Luu, C.]] | ||
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[[Category: Tsai, J.]] | [[Category: Tsai, J.]] | ||
[[Category: Wang, W.]] | [[Category: Wang, W.]] | ||
[[Category: West, B | [[Category: West, B L.]] | ||
[[Category: Zhang, C.]] | [[Category: Zhang, C.]] | ||
[[Category: kinase domain]] | [[Category: kinase domain]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:27:08 2008'' | ||
Revision as of 18:27, 21 February 2008
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Structural Characterization of autoinhibited c-Met kinase
OverviewOverview
Protein kinases are a large family of cell signaling mediators undergoing intensive research to identify inhibitors or modulators useful for medicine. As one strategy, small-molecule compounds that bind the active site with high affinity can be used to inhibit the enzyme activity. X-ray crystallography is a powerful method to reveal the structures of the kinase active sites, and thus aid in the design of high-affinity, selective inhibitors. However, a limitation still exists in the ability to produce purified kinases in amounts sufficient for crystallography. Furthermore, kinases exist in different conformation states as part of their normal regulation, and the ability to prepare crystals of kinases in these various states also remains a limitation. In this study, the c-Abl, c-Src, and c-Met kinases are produced in high yields in Escherichia coli by using a bicistronic vector encoding the PTP1B tyrosine phosphatase. A 100-fold lower dose of the inhibitor, Imatinib, was observed to inhibit the unphosphorylated form of c-Abl kinase prepared by using this vector, compared to the phosphorylated form produced without PTP1B, consistent with the known selectivity of this inhibitor for the unactivated conformation of the enzyme. Unphosphorylated c-Met kinase produced with this vector was used to obtain the crystal structure, at 2.15-A resolution, of the autoinhibited form of the kinase domain, revealing an intricate network of interactions involving c-Met residues documented previously to cause dysregulation when mutated in several cancers.
About this StructureAbout this Structure
2G15 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
ReferenceReference
Structural characterization of autoinhibited c-Met kinase produced by coexpression in bacteria with phosphatase., Wang W, Marimuthu A, Tsai J, Kumar A, Krupka HI, Zhang C, Powell B, Suzuki Y, Nguyen H, Tabrizizad M, Luu C, West BL, Proc Natl Acad Sci U S A. 2006 Mar 7;103(10):3563-8. Epub 2006 Feb 28. PMID:16537444
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