|
|
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.
 Previous Article | Next Article 
Submitted June 17, 2005
Accepted August 29, 2005
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*
Protein Crystallography Unit, Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria, Australia
Cytopia Research Pty Ltd, Baker Heart Research Institute, Melbourne, Victoria, Australia
* Corresponding author; email: jamie.rossjohn{at}med.monash.edu.au.
JAK2, a member of the Janus kinase (JAK) family of Protein Tyrosine Kinases (PTKs), is an important intracellular mediator of cytokine signalling. Mutations of the JAK2 gene are associated with hematological 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 protein tyrosine kinase (PTK) domain. We report the 2.0 A 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-one, 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:
|
|
|
|
 
L. Zhao, H. Dong, C. C. Zhang, L. Kinch, M. Osawa, M. Iacovino, N. V. Grishin, M. Kyba, and L. J.-s. Huang
A JAK2 Interdomain Linker Relays Epo Receptor Engagement Signals to Kinase Activation
J. Biol. Chem.,
September 25, 2009;
284(39):
26988 - 26998.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. G. Frey, C. M. I. Ahmed, R. Dabelic, L. D. Jager, E. N. Noon-Song, S. M. Haider, H. M. Johnson, and N. J. Bigley
HSV-1-Induced SOCS-1 Expression in Keratinocytes: Use of a SOCS-1 Antagonist to Block a Novel Mechanism of Viral Immune Evasion
J. Immunol.,
July 15, 2009;
183(2):
1253 - 1262.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. G. Mullighan, J. Zhang, R. C. Harvey, J. R. Collins-Underwood, B. A. Schulman, L. A. Phillips, S. K. Tasian, M. L. Loh, X. Su, W. Liu, et al.
JAK mutations in high-risk childhood acute lymphoblastic leukemia
PNAS,
June 9, 2009;
106(23):
9414 - 9418.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
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]
|
|
|
|
|
