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Blood, 1 August 2005, Vol. 106, No. 3, pp. 996-1002. Prepublished online as a Blood First Edition Paper on April 14, 2005; DOI 10.1182/blood-2005-02-0707. This Article Full Text (PDF) All Versions of this Article: 2005-02-0707v1 106/3/996    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Boggon, T. J Articles by Eck, M. J Search for Related Content PubMed PubMed Citation Articles by Boggon, T. J Articles by Eck, M. J Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted February 22, 2005 Accepted April 5, 2005 Crystal structure of the Jak3 kinase domain in complex with a staurosporine analogue Titus J Boggon, Yiqun Li, Paul W Manley, and Michael J Eck* Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA Novartis Institutes for Biomedical Research, CH-4002, Basel, Switzerland * Corresponding author; email: eck{at}red.dfci.harvard.edu. Jak (Janus Kinase) family non-receptor 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, c. Patients unable to signal via c 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 analogue AFN941. The kinase domain is in the active conformation, with both activation loop tyrosine residues phosphorylated. The phosphate group on pTyr 981 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Structure of a Janus kinase: molecular insights and prospects for optimizing a new class of immunosuppressants John J. O'Shea, Massimo Gadina, and Xiaomin Chen Blood 2005 106: 765-766. [Full Text] [PDF] This article has been cited by other articles: C. Haan, D. C. Kroy, S. Wuller, U. Sommer, T. Nocker, C. Rolvering, I. Behrmann, P. C. Heinrich, and S. Haan An Unusual Insertion in Jak2 Is Crucial for Kinase Activity and Differentially Affects Cytokine Responses J. Immunol., March 1, 2009; 182(5): 2969 - 2977. [Abstract] [Full Text] [PDF] R. L. Levine and D. G. Gilliland Myeloproliferative disorders Blood, September 15, 2008; 112(6): 2190 - 2198. [Abstract] [Full Text] [PDF] H. Cheng, J. A. Ross, J. A. Frost, and R. A. Kirken Phosphorylation of Human Jak3 at Tyrosines 904 and 939 Positively Regulates Its Activity Mol. Cell. Biol., April 1, 2008; 28(7): 2271 - 2282. [Abstract] [Full Text] [PDF] T. Mercher, G. Wernig, S. A. Moore, R. L. Levine, T.-L. Gu, S. Frohling, D. Cullen, R. D. Polakiewicz, O. A. Bernard, T. J. Boggon, et al. JAK2T875N is a novel activating mutation that results in myeloproliferative disease with features of megakaryoblastic leukemia in a murine bone marrow transplantation model Blood, October 15, 2006; 108(8): 2770 - 2779. [Abstract] [Full Text] [PDF] M. Azam, V. Nardi, W. C. Shakespeare, C. A. Metcalf III, R. S. Bohacek, Y. Wang, R. Sundaramoorthi, P. Sliz, D. R. Veach, W. G. Bornmann, et al. Activity of dual SRC-ABL inhibitors highlights the role of BCR/ABL kinase dynamics in drug resistance PNAS, June 13, 2006; 103(24): 9244 - 9249. [Abstract] [Full Text] [PDF] I. S. Lucet, E. Fantino, M. Styles, R. Bamert, O. Patel, S. E. Broughton, M. Walter, C. J. Burns, H. Treutlein, A. F. Wilks, et al. The structural basis of Janus kinase 2 inhibition by a potent and specific pan-Janus kinase inhibitor Blood, January 1, 2006; 107(1): 176 - 183. [Abstract] [Full Text] [PDF] M. Pesu, J. O'Shea, L. Hennighausen, and O. Silvennoinen Identification of an Acquired Mutation in Jak2 Provides Molecular Insights into the Pathogenesis of Myeloproliferative Disorders Mol. Interv., August 1, 2005; 5(4): 211 - 215. [Abstract] [Full Text] [PDF]

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