Interactions of LY333531 and other bisindolyl maleimide inhibitors with PDK1

David Komander, Gursant S. Kular, Alexander W. Schüttelkopf, Maria Deak, K. R. C. Prakash, Jennifer Bain, Matthew Elliott, Marta Garrido-Franco, Alan P. Kozikowski, Dario R. Alessi, Daan M. F. van Aalten

    Research output: Contribution to journalArticlepeer-review

    81 Citations (Scopus)


    LY333531, BIM-1, BIM-2, BIM-3, and BIM-8 are bisindolyl maleimide-based, nanomolar protein kinase C inhibitors. LY333531, a PKCβ-specific inhibitor, is in clinical trials against diabetes and cardiac ventricular hypertrophy complications. Specificity analysis with a panel of 29 protein kinases reveals that these bisindolyl maleimide inhibitors also inhibit PDK1, a key kinase from the insulin signaling pathway, albeit in the lower µM range. To understand the molecular basis of inhibition, the PDK1 kinase domain was cocrystallized with these bisindolyl maleimide inhibitors. The inhibitor complexes represent the first structural description of this class of compounds, revealing their unusual nonplanar conformation within the ATP binding site and also explaining the higher inhibitory potential of LY33331 compared to the BIM compounds toward PDK1. A combination of site-directed mutagenesis and essential dynamics analysis gives further insight into PDK1 and also PKC inhibition by these compounds, and may aid inhibitor design.

    Original languageEnglish
    Pages (from-to)215-226
    Number of pages12
    Issue number2
    Publication statusPublished - Feb 2004


    • 3-Phosphoinositide-Dependent Protein Kinases
    • Binding Sites
    • Crystallography, X-Ray
    • Enzyme Inhibitors/pharmacology
    • Indoles/pharmacology
    • Maleimides/pharmacology
    • Models, Molecular
    • Protein Kinase C/antagonists & inhibitors
    • Protein Structure, Tertiary
    • Protein-Serine-Threonine Kinases/antagonists & inhibitors
    • Signal Transduction


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