TY - JOUR
T1 - Interactions of LY333531 and Other Bisindolyl Maleimide Inhibitors with PDK1
AU - Komander, David
AU - Kular, Gursant S.
AU - Schüttelkopf, Alexander W.
AU - Deak, Maria
AU - Prakash, K. R.C.
AU - Bain, Jennifer
AU - Elliott, Matthew
AU - Garrido-Franco, Marta
AU - Kozikowski, Alan P.
AU - Alessi, Dario R.
AU - Van Aalten, Daan M.F.
N1 - Funding Information:
We would like to thank the European Synchrotron Radiation Facility for beam time at ID14-EH1 and ID14-EH2. D.K. is funded by an MRC Predoctoral Fellowship, M.G.F. was supported by an EMBO long-term fellowship (ALTF 752-2002), and D.M.F.v.A. is supported by a Wellcome Trust Career Development Research Fellowship. D.R.A. thanks the Association for International Cancer Research, Diabetes UK, the Medical Research Council, and the pharmaceutical companies AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novo-Nordisk, and Pfizer for supporting the Division of Signal Transduction Therapy unit in Dundee.
PY - 2004/2
Y1 - 2004/2
N2 - 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.
AB - 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.
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U2 - 10.1016/j.str.2004.01.005
DO - 10.1016/j.str.2004.01.005
M3 - Article
C2 - 14962382
AN - SCOPUS:10744233962
SN - 0969-2126
VL - 12
SP - 215
EP - 226
JO - Structure
JF - Structure
IS - 2
ER -