Dissecting specificity in the Janus Kinases: The structures of JAK-specific inhibitors complexed to the JAK1 and JAK2 protein tyrosine kinase domains

Williams, Neal K., Bamert, Rebecca S., Patel, Onisha, Wang, Christina, Walden, Patricia M., Wilks, Andrew F., Fantino, Emmanuelle, Rossjohn, Jamie and Lucet, Isabelle S. (2009) Dissecting specificity in the Janus Kinases: The structures of JAK-specific inhibitors complexed to the JAK1 and JAK2 protein tyrosine kinase domains. Journal of Molecular Biology, 387 1: 219-232. doi:10.1016/j.jmb.2009.01.041


Author Williams, Neal K.
Bamert, Rebecca S.
Patel, Onisha
Wang, Christina
Walden, Patricia M.
Wilks, Andrew F.
Fantino, Emmanuelle
Rossjohn, Jamie
Lucet, Isabelle S.
Title Dissecting specificity in the Janus Kinases: The structures of JAK-specific inhibitors complexed to the JAK1 and JAK2 protein tyrosine kinase domains
Journal name Journal of Molecular Biology   Check publisher's open access policy
ISSN 0022-2836
1089-8638
Publication date 2009-03-20
Sub-type Article (original research)
DOI 10.1016/j.jmb.2009.01.041
Volume 387
Issue 1
Start page 219
End page 232
Total pages 14
Place of publication London, United Kingdom
Publisher Academic Press
Language eng
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.
Keyword Protein tyrosine kinase
JAK1 kinase
JAK2 kinase
Crystal structure
Pan-JAK inhibitor
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Faculty of Health and Behavioural Sciences -- Publications
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