1i44
From Proteopedia
(New page: 200px<br /> <applet load="1i44" size="450" color="white" frame="true" align="right" spinBox="true" caption="1i44, resolution 2.40Å" /> '''CRYSTALLOGRAPHIC ST...) |
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| - | [[Image:1i44.gif|left|200px]]<br /> | + | [[Image:1i44.gif|left|200px]]<br /><applet load="1i44" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="1i44" size=" | + | |
caption="1i44, resolution 2.40Å" /> | caption="1i44, resolution 2.40Å" /> | ||
'''CRYSTALLOGRAPHIC STUDIES OF AN ACTIVATION LOOP MUTANT OF THE INSULIN RECEPTOR TYROSINE KINASE'''<br /> | '''CRYSTALLOGRAPHIC STUDIES OF AN ACTIVATION LOOP MUTANT OF THE INSULIN RECEPTOR TYROSINE KINASE'''<br /> | ||
==Overview== | ==Overview== | ||
| - | The tyrosine kinase domain of the insulin receptor is subject to | + | The tyrosine kinase domain of the insulin receptor is subject to autoinhibition in the unphosphorylated basal state via steric interactions involving the activation loop. A mutation in the activation loop designed to relieve autoinhibition, Asp-1161 --> Ala, substantially increases the ability of the unphosphorylated kinase to bind ATP. The crystal structure of this mutant in complex with an ATP analog has been determined at 2.4-A resolution. The structure shows that the active site is unobstructed, but the end of the activation loop is disordered and therefore the binding site for peptide substrates is not fully formed. In addition, Phe-1151 of the protein kinase-conserved DFG motif, at the beginning of the activation loop, hinders closure of the catalytic cleft and proper positioning of alpha-helix C for catalysis. These results, together with viscometric kinetic measurements, suggest that peptide substrate binding induces a reconfiguration of the unphosphorylated activation loop prior to the catalytic step. The crystallographic and solution studies provide new insights into the mechanism by which the activation loop controls phosphoryl transfer as catalyzed by the insulin receptor. |
==Disease== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 1I44 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 ACP 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:// | + | 1I44 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=ACP:'>ACP</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=1I44 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: Frankel, M.]] | [[Category: Frankel, M.]] | ||
| - | [[Category: Hubbard, S | + | [[Category: Hubbard, S R.]] |
| - | [[Category: Kohanski, R | + | [[Category: Kohanski, R A.]] |
| - | [[Category: Till, J | + | [[Category: Till, J H.]] |
[[Category: ACP]] | [[Category: ACP]] | ||
[[Category: MG]] | [[Category: MG]] | ||
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[[Category: protein tyrosine kinase]] | [[Category: protein tyrosine kinase]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 13:07:46 2008'' |
Revision as of 11:07, 21 February 2008
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CRYSTALLOGRAPHIC STUDIES OF AN ACTIVATION LOOP MUTANT OF THE INSULIN RECEPTOR TYROSINE KINASE
Contents |
Overview
The tyrosine kinase domain of the insulin receptor is subject to autoinhibition in the unphosphorylated basal state via steric interactions involving the activation loop. A mutation in the activation loop designed to relieve autoinhibition, Asp-1161 --> Ala, substantially increases the ability of the unphosphorylated kinase to bind ATP. The crystal structure of this mutant in complex with an ATP analog has been determined at 2.4-A resolution. The structure shows that the active site is unobstructed, but the end of the activation loop is disordered and therefore the binding site for peptide substrates is not fully formed. In addition, Phe-1151 of the protein kinase-conserved DFG motif, at the beginning of the activation loop, hinders closure of the catalytic cleft and proper positioning of alpha-helix C for catalysis. These results, together with viscometric kinetic measurements, suggest that peptide substrate binding induces a reconfiguration of the unphosphorylated activation loop prior to the catalytic step. The crystallographic and solution studies provide new insights into the mechanism by which the activation loop controls phosphoryl transfer as catalyzed by the insulin receptor.
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
1I44 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
Crystallographic and solution studies of an activation loop mutant of the insulin receptor tyrosine kinase: insights into kinase mechanism., Till JH, Ablooglu AJ, Frankel M, Bishop SM, Kohanski RA, Hubbard SR, J Biol Chem. 2001 Mar 30;276(13):10049-55. Epub 2000 Dec 21. PMID:11124964
Page seeded by OCA on Thu Feb 21 13:07:46 2008
