A new regulatory switch in a JAK protein kinase

Members of the JAK family of protein kinases mediate signal transduction from cytokine receptors to transcription factor activation. Over‐stimulation of these pathways is causative in immune disorders like rheumatoid arthritis, psoriasis, lupus, and Crohn's disease. A search for selective inhibitors of a JAK kinase has led to our characterization of a previously unknown kinase conformation arising from presentation of Tyr962 of TYK2 to an inhibitory small molecule via an H‐bonding interaction. A small minority of protein kinase domains has a Tyrosine residue in this position within the αC‐β4 loop, and it is the only amino acid commonly seen here with H‐bonding potential. These discoveries will aid design of inhibitors that discriminate among the JAK family and more widely among protein kinases. Proteins 2011. © 2010 Wiley‐Liss, Inc.