Structural basis for selective inhibition of Src family kinases by PP1

Yi Liu, Anthony Bishop, Laurie Witucki, Brian Kraybill, Eiji Shimizu, Joe Tsien, Jeff Ubersax, Justin Blethrow, David O. Morgan, Kevan M. Shokat

Research output: Contribution to journalArticle

224 Citations (Scopus)

Abstract

Background: Small-molecule inhibitors that can target individual kinases are powerful tools for use in signal transduction research. It is difficult to find such compounds because of the enormous number of protein kinases and the highly conserved nature of their catalytic domains. Recently, a novel, potent, Src family selective tyrosine kinase inhibitor was reported (PP1). Here, we study the structural basis for this inhibitor's specificity for Src family kinases. Results: A single residue corresponding to Ile338 (v-Src numbering; Thr338 in c-Src) in Src family tyrosine kinases largely controls PP1's ability to inhibit protein kinases. Mutation of Ile338 to a larger residue such as methionine or phenylalanine in v-Src makes this inhibitor less potent. Conversely, mutation of Ile338 to alanine or glycine increases PP1's Potency. PP1 can inhibit Ser/Thr kinases if the residue corresponding to Ile338 in v-Src is mutated to glycine. We have accurately predicted several non-Src family kinases that are moderately (IC50 ~ 1 μM) inhibited by PP1, including c-Abl and the MAP kinase p38. Conclusions: Our mutagenesis studies of the ATP-binding site in both tyrosine kinases and Ser/Thr kinases explain why PP1 is a specific inhibitor of Src family tyrosine kinases. Determination of the structural basis of inhibitor specificity will aid in the design of more potent and more selective protein kinase inhibitors. The ability to desensitize a particular kinase to PP1 inhibition of residue 338 or conversely to sensitize a kinase to PP1 inhibition by mutation should provide a useful basis for chemical genetic studies of kinase signal transduction.

Original languageEnglish (US)
Pages (from-to)671-678
Number of pages8
JournalChemistry and Biology
Volume6
Issue number9
DOIs
StatePublished - Sep 1999

Fingerprint

src-Family Kinases
Phosphotransferases
Signal transduction
Protein-Tyrosine Kinases
Glycine
Protein Kinases
Mutation
Signal Transduction
Mutagenesis
p38 Mitogen-Activated Protein Kinases
Protein Kinase Inhibitors
Phenylalanine
Alanine
Methionine
Inhibitory Concentration 50
Catalytic Domain
Adenosine Triphosphate
Binding Sites
Molecules
Research

Keywords

  • Kinase inhibitor
  • Modeling
  • PP1
  • Selective
  • Src

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

Cite this

Liu, Y., Bishop, A., Witucki, L., Kraybill, B., Shimizu, E., Tsien, J., ... Shokat, K. M. (1999). Structural basis for selective inhibition of Src family kinases by PP1. Chemistry and Biology, 6(9), 671-678. https://doi.org/10.1016/S1074-5521(99)80118-5

Structural basis for selective inhibition of Src family kinases by PP1. / Liu, Yi; Bishop, Anthony; Witucki, Laurie; Kraybill, Brian; Shimizu, Eiji; Tsien, Joe; Ubersax, Jeff; Blethrow, Justin; Morgan, David O.; Shokat, Kevan M.

In: Chemistry and Biology, Vol. 6, No. 9, 09.1999, p. 671-678.

Research output: Contribution to journalArticle

Liu, Y, Bishop, A, Witucki, L, Kraybill, B, Shimizu, E, Tsien, J, Ubersax, J, Blethrow, J, Morgan, DO & Shokat, KM 1999, 'Structural basis for selective inhibition of Src family kinases by PP1', Chemistry and Biology, vol. 6, no. 9, pp. 671-678. https://doi.org/10.1016/S1074-5521(99)80118-5
Liu, Yi ; Bishop, Anthony ; Witucki, Laurie ; Kraybill, Brian ; Shimizu, Eiji ; Tsien, Joe ; Ubersax, Jeff ; Blethrow, Justin ; Morgan, David O. ; Shokat, Kevan M. / Structural basis for selective inhibition of Src family kinases by PP1. In: Chemistry and Biology. 1999 ; Vol. 6, No. 9. pp. 671-678.
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