1UVR

Structure of human PDK1 kinase domain in complex with BIM-8

Summary for 1UVR

• Entry DOI: 10.2210/pdb1uvr/pdb
• Related: 1H1W 1OKY 1OKZ 1UU3 1UU7 1UU8 1UU9
• Descriptor: 3-PHOSPHOINOSITIDE DEPENDENT PROTEIN KINASE-1, GLYCEROL, SULFATE ION, ... (5 entities in total)
• Functional Keywords: protein kinase, pkb, pdk1, inhibitor, ly333531, bisindolyl maleimide, bim-8, diabetes, cancer, transferase
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 1
• Total formula weight: 34971.93

Authors

Komander, D.,Garrido-Franco, M.,Kular, G.S.,Schuttelkopf, A.W.,Deak, M.,Prakash, K.R.,Bain, J.,Elliot, M.,Kozikowski, A.P.,Alessi, D.R.,Van Aalten, D.M.F. (deposition date: 2004-01-22, release date: 2004-03-04, Last modification date: 2024-11-13)

Primary citation

Komander, D.,Kular, G.S.,Schuttelkopf, A.W.,Deak, M.,Prakash, K.R.,Bain, J.,Elliot, M.,Garrido-Franco, M.,Kozikowski, A.P.,Alessi, D.R.,Van Aalten, D.M.F.
Interactions of Ly333531 and Other Bisindolyl Maleimide Inhibitors with Pdk1
Structure, 12:215-, 2004

PubMed Abstract: 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.

PubMed: 14962382
DOI: 10.1016/J.STR.2004.01.005

Experimental method

X-RAY DIFFRACTION (2.81 Å)