1p14
From Proteopedia
(New page: 200px<br /> <applet load="1p14" size="450" color="white" frame="true" align="right" spinBox="true" caption="1p14, resolution 1.90Å" /> '''Crystal structure o...) |
|||
| Line 1: | Line 1: | ||
| - | [[Image:1p14.gif|left|200px]]<br /> | + | [[Image:1p14.gif|left|200px]]<br /><applet load="1p14" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="1p14" size=" | + | |
caption="1p14, resolution 1.90Å" /> | caption="1p14, resolution 1.90Å" /> | ||
'''Crystal structure of a catalytic-loop mutant of the insulin receptor tyrosine kinase'''<br /> | '''Crystal structure of a catalytic-loop mutant of the insulin receptor tyrosine kinase'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Tyrosine 984 in the juxtamembrane region of the insulin receptor, between | + | Tyrosine 984 in the juxtamembrane region of the insulin receptor, between the transmembrane helix and the cytoplasmic tyrosine kinase domain, is conserved among all insulin receptor-like proteins from hydra to humans. Crystallographic studies of the tyrosine kinase domain and proximal juxtamembrane region reveal that Tyr-984 interacts with several other conserved residues in the N-terminal lobe of the kinase domain, stabilizing a catalytically nonproductive position of alpha-helix C. Steady-state kinetics measurements on the soluble kinase domain demonstrate that replacement of Tyr-984 with phenylalanine results in a 4-fold increase in kcat in the unphosphorylated (basal state) enzyme. Moreover, mutation of Tyr-984 in the full-length insulin receptor results in significantly elevated receptor phosphorylation levels in cells, both in the absence of insulin and following insulin stimulation. These data demonstrate that Tyr-984 plays an important structural role in maintaining the quiescent, basal state of the insulin receptor. In addition, the structural studies suggest a possible target site for small molecule activators of the insulin receptor, with potential use in the treatment of noninsulin-dependent diabetes mellitus. |
==Disease== | ==Disease== | ||
| Line 11: | Line 10: | ||
==About this Structure== | ==About this Structure== | ||
| - | 1P14 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/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:// | + | 1P14 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/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=1P14 OCA]. |
==Reference== | ==Reference== | ||
| Line 18: | Line 17: | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Transferase]] | [[Category: Transferase]] | ||
| - | [[Category: Covino, N | + | [[Category: Covino, N D.]] |
| - | [[Category: Hubbard, S | + | [[Category: Hubbard, S R.]] |
[[Category: Li, S.]] | [[Category: Li, S.]] | ||
| - | [[Category: Stein, E | + | [[Category: Stein, E G.]] |
| - | [[Category: Till, J | + | [[Category: Till, J H.]] |
[[Category: catalysis]] | [[Category: catalysis]] | ||
[[Category: mutant]] | [[Category: mutant]] | ||
| Line 28: | Line 27: | ||
[[Category: tyrosine kinase]] | [[Category: tyrosine kinase]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:23:54 2008'' |
Revision as of 12:23, 21 February 2008
|
Crystal structure of a catalytic-loop mutant of the insulin receptor tyrosine kinase
Contents |
Overview
Tyrosine 984 in the juxtamembrane region of the insulin receptor, between the transmembrane helix and the cytoplasmic tyrosine kinase domain, is conserved among all insulin receptor-like proteins from hydra to humans. Crystallographic studies of the tyrosine kinase domain and proximal juxtamembrane region reveal that Tyr-984 interacts with several other conserved residues in the N-terminal lobe of the kinase domain, stabilizing a catalytically nonproductive position of alpha-helix C. Steady-state kinetics measurements on the soluble kinase domain demonstrate that replacement of Tyr-984 with phenylalanine results in a 4-fold increase in kcat in the unphosphorylated (basal state) enzyme. Moreover, mutation of Tyr-984 in the full-length insulin receptor results in significantly elevated receptor phosphorylation levels in cells, both in the absence of insulin and following insulin stimulation. These data demonstrate that Tyr-984 plays an important structural role in maintaining the quiescent, basal state of the insulin receptor. In addition, the structural studies suggest a possible target site for small molecule activators of the insulin receptor, with potential use in the treatment of noninsulin-dependent diabetes mellitus.
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
1P14 is a Single protein structure of sequence from Homo sapiens. 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
Structural and biochemical evidence for an autoinhibitory role for tyrosine 984 in the juxtamembrane region of the insulin receptor., Li S, Covino ND, Stein EG, Till JH, Hubbard SR, J Biol Chem. 2003 Jul 11;278(28):26007-14. Epub 2003 Apr 21. PMID:12707268
Page seeded by OCA on Thu Feb 21 14:23:54 2008
Categories: Homo sapiens | Single protein | Transferase | Covino, N D. | Hubbard, S R. | Li, S. | Stein, E G. | Till, J H. | Catalysis | Mutant | Receptor | Tyrosine kinase
