1i44

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spinqualitylabelsall models 1i44, resolution 2.40Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

CRYSTALLOGRAPHIC STUDIES OF AN ACTIVATION LOOP MUTANT OF THE INSULIN RECEPTOR TYROSINE KINASE

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

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 MG and ACP 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

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