Title |
Dissecting Specificity in the Janus Kinases: The Structures of JAK-Specific Inhibitors Complexed to the JAK1 and JAK2 Protein Tyrosine Kinase Domains
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Published in |
Journal of Molecular Biology, January 2009
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DOI | 10.1016/j.jmb.2009.01.041 |
Pubmed ID | |
Authors |
Neal K. Williams, Rebecca S. Bamert, Onisha Patel, Christina Wang, Patricia M. Walden, Andrew F. Wilks, Emmanuelle Fantino, Jamie Rossjohn, Isabelle S. Lucet |
Abstract |
The Janus kinases (JAKs) are a pivotal family of protein tyrosine kinases (PTKs) that play prominent roles in numerous cytokine signaling pathways, with aberrant JAK activity associated with a variety of hematopoietic malignancies, cardiovascular diseases and immune-related disorders. Whereas the structures of the JAK2 and JAK3 PTK domains have been determined, the structure of the JAK1 PTK domain is unknown. Here, we report the high-resolution crystal structures of the "active form" of the JAK1 PTK domain in complex with two JAK inhibitors, a tetracyclic pyridone 2-t-butyl-9-fluoro-3,6-dihydro-7H-benz[h]-imidaz[4,5-f]isoquinoline-7-one (CMP6) and (3R,4R)-3-[4-methyl-3-[N-methyl-N-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl]-3-oxopropionitrile (CP-690,550), and compare them with the corresponding JAK2 PTK inhibitor complexes. Both inhibitors bound in a similar manner to JAK1, namely buried deep within a constricted ATP-binding site, thereby providing a basis for the potent inhibition of JAK1. As expected, the mode of inhibitor binding in JAK1 was very similar to that observed in JAK2, highlighting the challenges in developing JAK-specific inhibitors that target the ATP-binding site. Nevertheless, differences surrounding the JAK1 and JAK2 ATP-binding sites were apparent, thereby providing a platform for the rational design of JAK2- and JAK1-specific inhibitors. |
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Geographical breakdown
Country | Count | As % |
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Germany | 1 | <1% |
Netherlands | 1 | <1% |
United Kingdom | 1 | <1% |
Belgium | 1 | <1% |
Japan | 1 | <1% |
Unknown | 173 | 97% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Researcher | 37 | 21% |
Student > Ph. D. Student | 30 | 17% |
Student > Master | 19 | 11% |
Student > Bachelor | 17 | 10% |
Other | 14 | 8% |
Other | 20 | 11% |
Unknown | 41 | 23% |
Readers by discipline | Count | As % |
---|---|---|
Agricultural and Biological Sciences | 36 | 20% |
Chemistry | 29 | 16% |
Biochemistry, Genetics and Molecular Biology | 22 | 12% |
Medicine and Dentistry | 17 | 10% |
Pharmacology, Toxicology and Pharmaceutical Science | 11 | 6% |
Other | 20 | 11% |
Unknown | 43 | 24% |