1gag
From Proteopedia
(New page: 200px<br /> <applet load="1gag" size="450" color="white" frame="true" align="right" spinBox="true" caption="1gag, resolution 2.7Å" /> '''CRYSTAL STRUCTURE OF...) |
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| - | [[Image:1gag.gif|left|200px]]<br /> | + | [[Image:1gag.gif|left|200px]]<br /><applet load="1gag" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="1gag" size=" | + | |
caption="1gag, resolution 2.7Å" /> | caption="1gag, resolution 2.7Å" /> | ||
'''CRYSTAL STRUCTURE OF THE INSULIN RECEPTOR KINASE IN COMPLEX WITH A BISUBSTRATE INHIBITOR'''<br /> | '''CRYSTAL STRUCTURE OF THE INSULIN RECEPTOR KINASE IN COMPLEX WITH A BISUBSTRATE INHIBITOR'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Protein kinase inhibitors have applications as anticancer therapeutic | + | Protein kinase inhibitors have applications as anticancer therapeutic agents and biological tools in cell signaling. Based on a phosphoryl transfer mechanism involving a dissociative transition state, a potent and selective bisubstrate inhibitor for the insulin receptor tyrosine kinase was synthesized by linking ATPgammaS to a peptide substrate analog via a two-carbon spacer. The compound was a high affinity competitive inhibitor against both nucleotide and peptide substrates and showed a slow off-rate. A crystal structure of this inhibitor bound to the tyrosine kinase domain of the insulin receptor confirmed the key design features inspired by a dissociative transition state, and revealed that the linker takes part in the octahedral coordination of an active site Mg2+. These studies suggest a general strategy for the development of selective protein kinase inhibitors. |
==Disease== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 1GAG 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 MG and 112 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:// | + | 1GAG 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=MG:'>MG</scene> and <scene name='pdbligand=112:'>112</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=1GAG OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Transferase]] | [[Category: Transferase]] | ||
| - | [[Category: Ablooglu, A | + | [[Category: Ablooglu, A J.]] |
| - | [[Category: Cole, P | + | [[Category: Cole, P A.]] |
| - | [[Category: Hubbard, S | + | [[Category: Hubbard, S R.]] |
| - | [[Category: Kohanski, R | + | [[Category: Kohanski, R A.]] |
[[Category: Parang, K.]] | [[Category: Parang, K.]] | ||
| - | [[Category: Till, J | + | [[Category: Till, J H.]] |
[[Category: 112]] | [[Category: 112]] | ||
[[Category: MG]] | [[Category: MG]] | ||
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[[Category: tyrosine kinase]] | [[Category: tyrosine kinase]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:48:00 2008'' |
Revision as of 10:48, 21 February 2008
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CRYSTAL STRUCTURE OF THE INSULIN RECEPTOR KINASE IN COMPLEX WITH A BISUBSTRATE INHIBITOR
Contents |
Overview
Protein kinase inhibitors have applications as anticancer therapeutic agents and biological tools in cell signaling. Based on a phosphoryl transfer mechanism involving a dissociative transition state, a potent and selective bisubstrate inhibitor for the insulin receptor tyrosine kinase was synthesized by linking ATPgammaS to a peptide substrate analog via a two-carbon spacer. The compound was a high affinity competitive inhibitor against both nucleotide and peptide substrates and showed a slow off-rate. A crystal structure of this inhibitor bound to the tyrosine kinase domain of the insulin receptor confirmed the key design features inspired by a dissociative transition state, and revealed that the linker takes part in the octahedral coordination of an active site Mg2+. These studies suggest a general strategy for the development of selective protein kinase inhibitors.
Disease
Known diseases associated with this structure: Diabetes mellitus, insulin-resistant, with acanthosis nigricans OMIM:[147670], Hyperinsulinemic hypoglycemia, familial, 5 OMIM:[147670], Leprechaunism OMIM:[147670], Rabson-Mendenhall syndrome OMIM:[147670]
About this Structure
1GAG 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
Mechanism-based design of a protein kinase inhibitor., Parang K, Till JH, Ablooglu AJ, Kohanski RA, Hubbard SR, Cole PA, Nat Struct Biol. 2001 Jan;8(1):37-41. PMID:11135668
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