1UU3
Structure of human PDK1 kinase domain in complex with LY333531
Summary for 1UU3
Entry DOI | 10.2210/pdb1uu3/pdb |
Related | 1H1W 1OKY 1OKZ 1UU7 1UU8 1UU9 1UVR |
Descriptor | 3-PHOSPHOINOSITIDE DEPENDENT PROTEIN KINASE-1, GLYCEROL, SULFATE ION, ... (5 entities in total) |
Functional Keywords | protein kinase, pkb, pdk1, inhibitor, ly333531, diabetes, cancer, transferase, serine/threonine-protein kinase |
Biological source | HOMO SAPIENS (HUMAN) |
Total number of polymer chains | 1 |
Total formula weight | 37376.43 |
Authors | 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. (deposition date: 2003-12-15, release date: 2004-03-04, Last modification date: 2023-12-13) |
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 Cited by 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: 14962382DOI: 10.1016/J.STR.2004.01.005 PDB entries with the same primary citation |
Experimental method | X-RAY DIFFRACTION (1.7 Å) |
Structure validation
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