Biochemistry: Structural bioinformatics-based design of selective, irreversible kinase inhibitors

Michael S. Cohen, Chao Zhang, Kevan M. Shokat, Jack Taunton

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)1318-1321
Number of pages4
JournalScience
Volume308
Issue number5726
DOIs
StatePublished - May 27 2005

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