SEARCH:   Advanced

Blood, 1 January 2006, Vol. 107, No. 1, pp. 176-183. Prepublished online as a Blood First Edition Paper on September 20, 2005; DOI 10.1182/blood-2005-06-2413. This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 2005-06-2413v1 107/1/176    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map 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 Lucet, I. S. Articles by Rossjohn, J. Search for Related Content PubMed PubMed Citation Articles by Lucet, I. S. Articles by Rossjohn, J. Related Collections Hematopoiesis and Stem Cells Immunobiology Oncogenes and Tumor Suppressors Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY The structural basis of Janus kinase 2 inhibition by a potent and specific pan-Janus kinase inhibitor Isabelle S. Lucet, Emmanuelle Fantino, Michelle Styles, Rebecca Bamert, Onisha Patel, Sophie E. Broughton, Mark Walter, Christopher J. Burns, Herbert Treutlein, Andrew F. Wilks, and Jamie Rossjohn From the Protein Crystallography Unit, Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton; and Cytopia Research Pty Ltd, Baker Heart Research Institute, Melbourne, Victoria, Australia. JAK2, a member of the Janus kinase (JAK) family of protein tyrosine kinases (PTKs), is an important intracellular mediator of cytokine signaling. Mutations of the JAK2 gene are associated with hematologic cancers, and aberrant JAK activity is also associated with a number of immune diseases, including rheumatoid arthritis. Accordingly, the development of JAK2-specific inhibitors has tremendous clinical relevance. Critical to the function of JAK2 is its PTK domain. We report the 2.0 Å crystal structure of the active conformation of the JAK2 PTK domain in complex with a high-affinity, pan-JAK inhibitor that appears to bind via an induced fit mechanism. This inhibitor, the tetracyclic pyridone 2-tert-butyl-9-fluoro-3,6-dihydro-7H-benz[h]-imidaz[4,5-f]isoquinoline-7-1, was buried deep within a constricted ATP-binding site, in which extensive interactions, including residues that are unique to JAK2 and the JAK family, are made with the inhibitor. We present a structural basis of high-affinity JAK-specific inhibition that will undoubtedly provide an invaluable tool for the further design of novel, potent, and specific therapeutics against the JAK family. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: D. B. Lipka, L. S. Hoffmann, F. Heidel, B. Markova, M.-C. Blum, F. Breitenbuecher, S. Kasper, T. Kindler, R. L. Levine, C. Huber, et al. LS104, a non-ATP-competitive small-molecule inhibitor of JAK2, is potently inducing apoptosis in JAK2V617F-positive cells Mol. Cancer Ther., May 1, 2008; 7(5): 1176 - 1184. [Abstract] [Full Text] [PDF] T. H. Elsasser, T. J. Caperna, C-J. Li, S. Kahl, and J. L. Sartin Critical control points in the impact of the proinflammatory immune response on growth and metabolism J Anim Sci, April 1, 2008; 86(14_suppl): E105 - E125. [Abstract] [Full Text] [PDF] T. H. Elsasser, C.-J. Li, T. J. Caperna, S. Kahl, and W. F. Schmidt Growth Hormone (GH)-Associated Nitration of Janus Kinase-2 at the 1007Y-1008Y Epitope Impedes Phosphorylation at This Site: Mechanism for and Impact of a GH, AKT, and Nitric Oxide Synthase Axis on GH Signal Transduction Endocrinology, August 1, 2007; 148(8): 3792 - 3802. [Abstract] [Full Text] [PDF] L. M. Scott, W. Tong, R. L. Levine, M. A. Scott, P. A. Beer, M. R. Stratton, P. A. Futreal, W. N. Erber, M. F. McMullin, C. N. Harrison, et al. JAK2 Exon 12 Mutations in Polycythemia Vera and Idiopathic Erythrocytosis N. Engl. J. Med., February 1, 2007; 356(5): 459 - 468. [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] J. H. Kurzer, P. Saharinen, O. Silvennoinen, and C. Carter-Su Binding of SH2-B Family Members within a Potential Negative Regulatory Region Maintains JAK2 in an Active State. Mol. Cell. Biol., September 1, 2006; 26(17): 6381 - 6394. [Abstract] [Full Text] [PDF] P. Sidon, P. Heimann, F. Lambert, B. Dessars, V. Robin, and H. El Housni Combined Locked Nucleic Acid and Molecular Beacon Technologies for Sensitive Detection of the JAK2V617F Somatic Single-Base Sequence Variant. Clin. Chem., July 1, 2006; 52(7): 1436 - 1438. [Full Text] [PDF] E. Jacobsen Anaplastic Large-Cell Lymphoma, T-/Null-Cell Type Oncologist, July 1, 2006; 11(7): 831 - 840. [Abstract] [Full Text] [PDF]

	Copyright © 2006 by American Society of Hematology         Online ISSN: 1528-0020