1y57
From Proteopedia
(New page: 200px<br /> <applet load="1y57" size="450" color="white" frame="true" align="right" spinBox="true" caption="1y57, resolution 1.91Å" /> '''Structure of unphos...) |
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| - | [[Image:1y57.gif|left|200px]]<br /> | + | [[Image:1y57.gif|left|200px]]<br /><applet load="1y57" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="1y57" size=" | + | |
caption="1y57, resolution 1.91Å" /> | caption="1y57, resolution 1.91Å" /> | ||
'''Structure of unphosphorylated c-Src in complex with an inhibitor'''<br /> | '''Structure of unphosphorylated c-Src in complex with an inhibitor'''<br /> | ||
==Overview== | ==Overview== | ||
| - | The regulation of the activity of Abl and Src family tyrosine kinases is | + | The regulation of the activity of Abl and Src family tyrosine kinases is mediated by intramolecular interactions between the SH3, SH2, and kinase (SH1) domains. We have determined the crystal structure of an unphosphorylated form of c-Src in which the SH2 domain is not bound to the C-terminal tail. This results in an open structure where the kinase domain adopts an active conformation and the C terminus binds within a hydrophobic pocket in the C-terminal lobe. NMR binding studies support the hypothesis that an N-terminal myristate could bind in this pocket, as observed for Abl, suggesting that c-Src may also be regulated by myristate binding. In addition, the structure contains a des-methyl analog of the antileukemia drug imatinib (STI571; Gleevec). This structure reveals why the drug shows a low affinity for active kinase conformations, contributing to its excellent kinase selectivity profile. |
==Disease== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 1Y57 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with SO4 and MPZ as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Transferase Transferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 and 2.7.10.2 2.7.10.1 and 2.7.10.2] Full crystallographic information is available from [http:// | + | 1Y57 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=SO4:'>SO4</scene> and <scene name='pdbligand=MPZ:'>MPZ</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Transferase Transferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 and 2.7.10.2 2.7.10.1 and 2.7.10.2] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1Y57 OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Transferase]] | [[Category: Transferase]] | ||
| - | [[Category: Cowan-Jacob, S | + | [[Category: Cowan-Jacob, S W.]] |
[[Category: Fabbro, D.]] | [[Category: Fabbro, D.]] | ||
[[Category: Fendrich, G.]] | [[Category: Fendrich, G.]] | ||
[[Category: Jahnke, W.]] | [[Category: Jahnke, W.]] | ||
[[Category: Liebetanz, J.]] | [[Category: Liebetanz, J.]] | ||
| - | [[Category: Manley, P | + | [[Category: Manley, P W.]] |
[[Category: Meyer, T.]] | [[Category: Meyer, T.]] | ||
[[Category: MPZ]] | [[Category: MPZ]] | ||
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[[Category: sh3]] | [[Category: sh3]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:01:58 2008'' |
Revision as of 14:02, 21 February 2008
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Structure of unphosphorylated c-Src in complex with an inhibitor
Contents |
Overview
The regulation of the activity of Abl and Src family tyrosine kinases is mediated by intramolecular interactions between the SH3, SH2, and kinase (SH1) domains. We have determined the crystal structure of an unphosphorylated form of c-Src in which the SH2 domain is not bound to the C-terminal tail. This results in an open structure where the kinase domain adopts an active conformation and the C terminus binds within a hydrophobic pocket in the C-terminal lobe. NMR binding studies support the hypothesis that an N-terminal myristate could bind in this pocket, as observed for Abl, suggesting that c-Src may also be regulated by myristate binding. In addition, the structure contains a des-methyl analog of the antileukemia drug imatinib (STI571; Gleevec). This structure reveals why the drug shows a low affinity for active kinase conformations, contributing to its excellent kinase selectivity profile.
Disease
Known disease associated with this structure: Colon cancer, advanced OMIM:[190090]
About this Structure
1Y57 is a Single protein structure of sequence from Homo sapiens with and as ligands. Active as Transferase, with EC number and 2.7.10.2 2.7.10.1 and 2.7.10.2 Full crystallographic information is available from OCA.
Reference
The crystal structure of a c-Src complex in an active conformation suggests possible steps in c-Src activation., Cowan-Jacob SW, Fendrich G, Manley PW, Jahnke W, Fabbro D, Liebetanz J, Meyer T, Structure. 2005 Jun;13(6):861-71. PMID:15939018
Page seeded by OCA on Thu Feb 21 16:01:58 2008
Categories: Homo sapiens | Single protein | Transferase | Cowan-Jacob, S W. | Fabbro, D. | Fendrich, G. | Jahnke, W. | Liebetanz, J. | Manley, P W. | Meyer, T. | MPZ | SO4 | Kinase structure | Sh2 | Sh3
