1uu3

File:1uu3.gif

spinqualitylabelsall models 1uu3, resolution 1.70Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

STRUCTURE OF HUMAN PDK1 KINASE DOMAIN IN COMPLEX WITH LY333531

OverviewOverview

LY333531, BIM-1, BIM-2, BIM-3, and BIM-8 are bisindolyl maleimide-based, nanomolar protein kinase C inhibitors. LY333531, a PKCbeta-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, microM 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.

About this StructureAbout this Structure

1UU3 is a Single protein structure of sequence from Homo sapiens with SO4, LY4 and GOL as ligands. Active as Transferred entry: 2.7.11.1, with EC number 2.7.1.37 Structure known Active Site: AC1. Full crystallographic information is available from OCA.

ReferenceReference

Interactions of LY333531 and other bisindolyl maleimide inhibitors with PDK1., Komander D, Kular GS, Schuttelkopf AW, Deak M, Prakash KR, Bain J, Elliott M, Garrido-Franco M, Kozikowski AP, Alessi DR, van Aalten DM, Structure. 2004 Feb;12(2):215-26. PMID:14962382

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