1yvj

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Revision as of 18:18, 12 November 2007

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spinqualitylabelsall models 1yvj, resolution 2.55Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Crystal structure of the Jak3 kinase domain in complex with a staurosporine analogue

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

Jak (Janus kinase) family nonreceptor tyrosine kinases are central, mediators of cytokine signaling. The Jak kinases exhibit distinct cytokine, receptor association profiles and so transduce different signals. Jak3, expression is limited to the immune system, where it plays a key role in, signal transduction from cytokine receptors containing the common, gamma-chain, gammac. Patients unable to signal via gammac present with, severe combined immunodeficiency (SCID). The finding that Jak3 mutations, result in SCID has made it a target for development of lymphocyte-specific, immunosuppressants. Here, we present the crystal structure of the Jak3, kinase domain in complex with staurosporine analog AFN941. The kinase, domain is in the active conformation, with both activation loop tyrosine, residues phosphorylated. The phosphate group on pTyr981 in the activation, loop is in part coordinated by an arginine residue in the regulatory, C-helix, suggesting a direct mechanism by which the active position of the, C-helix is induced by phosphorylation of the activation loop. Such a, direct coupling has not been previously observed in tyrosine kinases and, may be unique to Jak kinases. The crystal structure provides a detailed, view of the Jak3 active site and will facilitate computational and, structure-directed approaches to development of Jak3-specific inhibitors.

Disease

Known disease associated with this structure: SCID, autosomal recessive, T-negative/B-positive type OMIM:[600173]

About this Structure

1YVJ is a Single protein structure of sequence from Homo sapiens with DTV and 4ST 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

Crystal structure of the Jak3 kinase domain in complex with a staurosporine analog., Boggon TJ, Li Y, Manley PW, Eck MJ, Blood. 2005 Aug 1;106(3):996-1002. Epub 2005 Apr 14. PMID:15831699

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