1UU8

Structure of human PDK1 kinase domain in complex with BIM-1

1UU8 の概要

• エントリーDOI: 10.2210/pdb1uu8/pdb
• 関連するPDBエントリー: 1H1W 1OKY 1OKZ 1UU3 1UU7 1UU9 1UVR
• 分子名称: 3-PHOSPHOINOSITIDE DEPENDENT PROTEIN KINASE-1, GLYCEROL, SULFATE ION, ... (5 entities in total)
• 機能のキーワード: protein kinase, pkb, pdk1, inhibitor, ly333531, bisindolyl maleimide, bim-1, diabetes, cancer, transferase, serine/threonine-protein kinase
• 由来する生物種: HOMO SAPIENS (HUMAN)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 36844.02

構造登録者

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. (登録日: 2003-12-16, 公開日: 2004-03-04, 最終更新日: 2024-10-16)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.5 Å)