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

74 Scopus citations


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 (US)
Pages (from-to)215-226
Number of pages12
Issue number2
StatePublished - Feb 2004
Externally publishedYes

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology


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