The Janus family of protein tyrosine kinases is comprised of four members: JAK-1, JAK-2, JAK-3 and Tyk-2. These kinases provide membrane proximal signalling through association with type 1 and type 2 cytokine receptors, phosphorylating and activating Signal Transducers and Activators of Transcription proteins (STATs) in response to cytokine binding. Expression of JAK-3 is predominantly restricted to haematopoietic cells, whilst the other family members are ubiquitously expressed. Inhibitors of these kinases have received interest since aberrant JAK activity has been associated with a variety of hematopoietic malignancies, cardiovascular diseases and immune-related disorders. A number of clinical studies are in progress to evaluate JAK inhibitors in transplantation, myelofibrosis, polycythaemia vera and essential thrombocythaemia.
Crystal structures of the kinase domains of JAK-2 and JAK-3 have previously been solved, enabling structure-based design of inhibitors. Now collaborators at Cytopia Research and Monash University have published the high-resolution crystal structure of the JAK-1 kinase domain. Whilst the ATP-binding sites of protein kinases are highly conserved, particularly amongst family members, the researchers have identified subtle differences surrounding the JAK1 and JAK2 ATP-binding sites. There is no doubt that developing JAK-1 or JAK-2 selective inhibitors (at the ATP-site) will be challenging, but the new data at least suggest that it could be possible. Whether it is necessary or desirable to achieve such selectivity is, as yet, unclear.
Full details are published in the Journal of Molecular Biology.
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