TY - JOUR
T1 - Biochemistry
T2 - Structural bioinformatics-based design of selective, irreversible kinase inhibitors
AU - Cohen, Michael S.
AU - Zhang, Chao
AU - Shokat, Kevan M.
AU - Taunton, Jack
PY - 2005/5/27
Y1 - 2005/5/27
N2 - The active sites of 491 human protein kinase domains are highly conserved, which makes the design of selective inhibitors a formidable challenge. We used a structural bioinformatics approach to identify two selectivity filters, a threonine and a cysteine, at defined positions in the active site of p90 ribosomal protein S6 kinase (RSK). A fluoromethylketone inhibitor, designed to exploit both selectivity filters, potently and selectively inactivated RSK1 and RSK2 in mammalian cells. Kinases with only one selectivity filter were resistant to the inhibitor, yet they became sensitized after genetic introduction of the second selectivity filter. Thus, two amino acids that distinguish RSK from other protein kinases are sufficient to confer inhibitor sensitivity.
AB - The active sites of 491 human protein kinase domains are highly conserved, which makes the design of selective inhibitors a formidable challenge. We used a structural bioinformatics approach to identify two selectivity filters, a threonine and a cysteine, at defined positions in the active site of p90 ribosomal protein S6 kinase (RSK). A fluoromethylketone inhibitor, designed to exploit both selectivity filters, potently and selectively inactivated RSK1 and RSK2 in mammalian cells. Kinases with only one selectivity filter were resistant to the inhibitor, yet they became sensitized after genetic introduction of the second selectivity filter. Thus, two amino acids that distinguish RSK from other protein kinases are sufficient to confer inhibitor sensitivity.
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U2 - 10.1126/science1108367
DO - 10.1126/science1108367
M3 - Article
C2 - 15919995
AN - SCOPUS:19744364796
SN - 0036-8075
VL - 308
SP - 1318
EP - 1321
JO - Science
JF - Science
IS - 5726
ER -