1yvj
From Proteopedia
(New page: 200px<br /> <applet load="1yvj" size="450" color="white" frame="true" align="right" spinBox="true" caption="1yvj, resolution 2.55Å" /> '''Crystal structure o...) |
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| - | [[Image:1yvj.gif|left|200px]]<br /> | + | [[Image:1yvj.gif|left|200px]]<br /><applet load="1yvj" size="350" color="white" frame="true" align="right" spinBox="true" |
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caption="1yvj, resolution 2.55Å" /> | caption="1yvj, resolution 2.55Å" /> | ||
'''Crystal structure of the Jak3 kinase domain in complex with a staurosporine analogue'''<br /> | '''Crystal structure of the Jak3 kinase domain in complex with a staurosporine analogue'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Jak (Janus kinase) family nonreceptor tyrosine kinases are central | + | 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== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 1YVJ 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 DTV and 4ST 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:// | + | 1YVJ 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=DTV:'>DTV</scene> and <scene name='pdbligand=4ST:'>4ST</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=1YVJ OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Transferase]] | [[Category: Transferase]] | ||
| - | [[Category: Boggon, T | + | [[Category: Boggon, T J.]] |
| - | [[Category: Eck, M | + | [[Category: Eck, M J.]] |
[[Category: Li, Y.]] | [[Category: Li, Y.]] | ||
| - | [[Category: Manley, P | + | [[Category: Manley, P W.]] |
[[Category: 4ST]] | [[Category: 4ST]] | ||
[[Category: DTV]] | [[Category: DTV]] | ||
[[Category: tyrosine kinase; scid; severe combined immunodeficiency; stat5; stat6; interleukin-2; common-gamma chain]] | [[Category: tyrosine kinase; scid; severe combined immunodeficiency; stat5; stat6; interleukin-2; common-gamma chain]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:09:33 2008'' |
Revision as of 14:09, 21 February 2008
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Crystal structure of the Jak3 kinase domain in complex with a staurosporine analogue
Contents |
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 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
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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