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Crystal Structure of the Jak3 Kinase Domain in Complex with a Staurosporine Analog

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Crystal Structure of the Jak3 Kinase Domain in Complex with a Staurosporine Analog From www.bloodjournal.org by guest on September 11, 2016. For personal use only. TRANSPLANTATION Crystal structure of the Jak3 kinase domain in complex with a staurosporine analog Titus J. Boggon, Yiqun Li, Paul W. Manley, and Michael J. Eck Jak (Janus kinase) family nonreceptor target for development of lymphocyte- tion of the activation loop. Such a direct tyrosine kinases are central mediators of specific immunosuppressants. Here, we coupling has not been previously ob- cytokine signaling. The Jak kinases ex- present the crystal structure of the Jak3 served in tyrosine kinases and may be hibit distinct cytokine receptor associa- kinase domain in complex with stauro- unique to Jak kinases. The crystal struc- tion profiles and so transduce different sporine analog AFN941. The kinase do- ture provides a detailed view of the Jak3 signals. Jak3 expression is limited to the main is in the active conformation, with active site and will facilitate computa- immune system, where it plays a key role both activation loop tyrosine residues tional and structure-directed approaches in signal transduction from cytokine re- phosphorylated. The phosphate group on to development of Jak3-specific inhibi- ceptors containing the common gamma- pTyr981 in the activation loop is in part tors. (Blood. 2005;106:996-1002) chain, ␥c. Patients unable to signal via ␥c coordinated by an arginine residue in the present with severe combined immunode- regulatory C-helix, suggesting a direct ficiency (SCID). The finding that Jak3 mechanism by which the active position mutations result in SCID has made it a of the C-helix is induced by phosphoryla- © 2005 by The American Society of Hematology Introduction The Janus kinase (Jak) family of cytoplasmic tyrosine kinases are regulation of diverse cell processes, including proliferation, differ- essential for signal transduction from a wide variety of cell-surface entiation, migration, and apoptosis.1,2 receptors. There are 4 members of the family in vertebrates: Jak1, In a significant number of patients with severe combined Jak2, Jak3, and tyrosine kinase 2 (Tyk2).1,2 Jak kinases share a immunodeficiency (SCID), the disease arises from mutations either characteristic domain architecture, which includes an amino- in the cytokine receptor common gamma-chain, ␥c, or in the terminal FERM domain (Band 4.1, Ezrin, Radixin, Moesin homol- interleukin receptor IL-7R which uses ␥c, or in Jak3 (accounting ogy domain), an src homology 2 (SH2)–like region, a pseudokinase for ϳ 50%, ϳ 10%, and ϳ 7%-14% of human SCIDs, respec- domain, and a carboxy-terminal kinase domain. Parts of these tively).4 The phenotype of patients with ␥c and Jak3 mutations is structural domains have historically been termed Jak homology virtually identical; they present with no T or natural killer cells and (JH) domains 1 through 7, based on primary sequence alignments. a normal number of poorly functioning B cells (TϪBϩNKϪSCID).5-8 The FERM domain mediates association with the cytoplasmic Human SCID patients do not produce specific antibodies in region of cytokine receptors and may also participate in catalytic response to in vivo antigenic challenge, and the disease usually regulation. The function and activity of the SH2-like region is presents in infants as an array of opportunistic infections and unclear. The pseudokinase (or JH2) domain is unique to Jak mortality in the first 2 years of life. Human SCID is currently kinases. This domain is thought to have a protein kinase fold but to treated by reconstitution of the immune defenses with hematopoi- lack catalytic activity, as residues critical for phosphotransfer are etic stem cell transplantation. The ␥c/Jak3 SCID phenotype is absent. The pseudokinase domain has been shown to be intrinsic to limited and specific to the immune system, and patients with SCID the autoregulation of Jak kinases via a direct interaction with the are otherwise healthy and display almost no symptoms following kinase domain.3 The JH1 kinase domain lies at the C-terminus and stem cell transplantation.8 The Jak3 mutations that give rise to is a functional tyrosine kinase. To date, no 3-dimensional structure SCID have been reviewed recently in O’Shea et al.4 has been reported for any portion of any of the Jak kinases. The profound immune-specific effects of disrupted Jak3 signal- A wide variety of cytokine receptor superfamily members ing highlight the possibility of therapeutic targeting of Jak3 as a signal via the Jak/Stat (signal transducer and activator of transcrip- highly specific mode of immune system suppression.9 Potentially, a tion) pathway, including granulocyte colony-stimulating factor Jak3-specific inhibitor would target the immune system by deplet- (G-CSF), thrombopoietin, the interferons, erythropoietin, and the ing natural killer and T cells through down-regulation of cell interleukins. The Jak/Stat pathway is consequently involved in proliferation. Jak3-specific inhibitors are being studied as From the Department of Biological Chemistry and Molecular Pharmacology, Scholar Award from the Leukemia and Lymphoma Society (M.J.E.). Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA; the An Inside Blood analysis of this article appears in the front of this issue. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA; and the Novartis Institutes for Biomedical Research, CH-4002 Basel, Switzerland. Reprints: Michael J. Eck, Rm SM 10-36, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA 02115; e-mail: [email protected]. Submitted February 22, 2005; accepted April 5, 2005. Prepublished online as The publication costs of this article were defrayed in part by page charge Blood First Edition Paper, April 14, 2005; DOI 10.1182/blood-2005-02-0707. payment. Therefore, and solely to indicate this fact, this article is hereby marked ‘‘advertisement’’ in accordance with 18 U.S.C. section 1734. Supported by an American Society of Hematology Basic Research Scholar Award (T.J.B.), by the National Institutes of Health (NIH; grant CA080942) (M.J.E.), and by a © 2005 by The American Society of Hematology 996 BLOOD, 1 AUGUST 2005 ⅐ VOLUME 106, NUMBER 3 From www.bloodjournal.org by guest on September 11, 2016. For personal use only. BLOOD, 1 AUGUST 2005 ⅐ VOLUME 106, NUMBER 3 CRYSTAL STRUCTURE OF JAK3 KINASE DOMAIN 997 supplements to current organ transplant rejection therapies and to supplemented with 5 mM DTT and 10% glycerol and then incubated treat T-cell–specific autoimmune diseases, including psoriasis, overnight with 5 ␮L of 3 mg/mL human ␣-thrombin (Enzyme Research, multiple sclerosis, inflammatory bowel disease, and rheumatoid South Bend, IN) at 4°C. Jak3 kinase domain was eluted; dialyzed against 20 arthritis.10 Jak-specific inhibitors may also be useful for treatment mM Tris-HCl, pH 8, 50 mM NaCl, 5 mM DTT, 10% glycerol; and loaded onto a Mono Q column (Amersham Biosciences AB). Jak3 kinase domain of hematologic and other malignancies that involve pathologic Jak 11 eluted at approximately 150 mM NaCl. For crystallization, the protein was activation. Activated translocated ets leukemia (TEL) protein/ concentrated to 5 mg/mL. Aliquots were flash-frozen in liquid nitrogen and Jak2 fusions are produced by chromosomal translocations in some stored at Ϫ80°C. The kinase domain was shown to be catalytically active in 12 human leukemias, and Jak activation has been shown to be a kinase assay using the T-cell receptor (TCR) ␨-chain as a substrate (T.J.B., transforming when activated by other tyrosine kinase oncogenes. unpublished observations, September 1, 2004). For example v- and breakpoint cluster region-abelson (BCR-Abl) activate the Jak/Stat signaling pathway.13-15 Thus Jak-specific Crystallization and diffraction data collection inhibitors may be useful to augment kinase-specific treatments Following incubation with inhibitor AFN941 for 1 hour on ice (5 ␮L protein such as imatinib mesylate (Novartis Pharma AG, Basel, Switzer- at 5 mg/mL, 0.25 ␮L AFN941 at 50 mM, and 0.2 ␮L DTT at 1 M) and land) for CML. A number of Jak-specific inhibitors are currently in centrifugation at 16 000 g for 30 minutes, crystallization trays were set up. clinical and preclinical trials,9 with CP-690550 (Pfizer, New York, Crystallization trays were set up at 4°C using hanging-drop vapor diffusion NY) showing some selectivity for Jak3 (IC50 [inhibitory concentra- methodology with reservoirs containing 50 mM Pipes (1,4-piperazinedi- tion 50%] Jak1, 112 nM; Jak2, 20 nM; Jak3, 1 nM) and ethanesulfonic acid) pH 6, 960 mM Na malonate pH 6, 1.6% glycerol, and demonstrating efficacy against organ allograft rejection.16 10 mM DTT. Crystallization drops contained 0.3 ␮L precipitant buffer and We describe here the crystal structure of the Jak3 kinase domain 0.5 ␮L protein solution. A crystal appeared after 2 weeks and grew to its ϫ ϫ ␮ in complex with a staurosporine-based inhibitor. The kinase is in an final dimension (100 100 200 m) in 4 weeks. The primitive orthor- ϭ ϭ ϭ active, doubly phosphorylated state. The structure provides mecha- hombic cell had dimensions a 46.3 Å, b 54.2 Å, and c 118.6 Å. For data collection the mother liquor in the drop was substituted with 2M Na nistic insights into Jak activation and provides a detailed view of malonate, pH 6. The crystal was flash frozen to 100K using an in-house the kinase that will facilitate development of Jak-specific inhibitors. cryostream. Data were collected at 100K in house on a Rigaku (The Woodlands, TX) RU300-RC rotating anode X-ray generator with Osmic Confocal Max-Flux (CMF12-38Cu6) optics and a Mar345dtb image plate area detector (Mar Research, Norderstedt, Germany). The data were Materials and methods processed in space group P212121 with DENZO and scaled using SCALE- PACK.20 Data are summarized in Table 1.
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