Dissecting Specificity in the Janus Kinases: The Structures of JAK-Specific Inhibitors Complexed to the JAK1 and JAK2 Protein Tyrosine Kinase Domains

Neal Kenneth Williams, Rebecca Samantha Bamert, Onisha Patel, Chunxiao Wang, Patricia M Walden, Andrew Frederick Wilks, Emmanuelle Fantino, Jamie Rossjohn, Isabelle S Lucet

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152 Citations (Scopus)

Abstract

The Janus kinases are a pivotal family of Protein Tyrosine Kinases (PTKs) that play prominent roles in numerous cytokine-signalling pathways, with aberrant JAK activity associated with a variety of hematopoietic malignancies, cardiovascular diseases and immune related disorders. Whereas the structures of JAK2 and JAK3 PTK domains have been determined, the structure of the JAK1 PTK domain was unknown. Here we report the high resolution crystal structures of the active-form of the JAK1 PTK domain in complex with two JAK kinase inhibitors, a tetracyclic pyridone 2-tert-butyl-9-fluoro-3,6-dihydro-7H-benz[h]-imidaz[4,5-f]isoquinoline-7-o ne (CMP6) and (3R,4R)-3-[4-methyl-3-[N-methyl-N-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]p iperidin-1-yl]-3-oxopropionitrile (CP-690,550) and compare them to 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.
Original languageEnglish
Pages (from-to)219 - 232
Number of pages14
JournalJournal of Molecular Biology
Volume387
Issue number1
DOIs
Publication statusPublished - 2009

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