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.
Department of Discovery Chemistry, Genentech, Inc, South San Francisco, California 94080, USA.
Vickie
V
Tsui
Paul
P
Gibbons
Mark
M
Ultsch
Kyle
K
Mortara
Christine
C
Chang
Wade
W
Blair
Rebecca
R
Pulk
Mark
M
Stanley
Melissa
M
Starovasnik
David
D
Williams
Maria
M
Lamers
Phillip
P
Leonard
Steven
S
Magnuson
Jun
J
Liang
Charles
C
Eigenbrot
D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D007546:Isoquinolines / Q000737:chemistry; D008958:Models, Molecular; D009154:Mutation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry; D017434:Protein Structure, Tertiary; D011804:Quinolines / Q000737:chemistry; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D053634:TYK2 Kinase / Q000037:antagonists & inhibitors / Q000737:chemistry*; D013876:Thiophenes / Q000737:chemistry
D007546:Isoquinolines; D047428:Protein Kinase Inhibitors; D011804:Quinolines; D011994:Recombinant Proteins; D013876:Thiophenes; D053634:TYK2 Kinase; C070139:TYK2 protein, human