1OKZ

Structure of human PDK1 kinase domain in complex with UCN-01

1OKZ の概要

• エントリーDOI: 10.2210/pdb1okz/pdb
• 関連するPDBエントリー: 1H1W 1OKY 1UU3 1UU7 1UU8 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, ucn-01, 7-hydroxy staurosporine, inhibitor, transferase, atp-binding, phosphorylation
• 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: 37014.10

構造登録者

Komander, D.,Kular, G.S.,Alessi, D.R.,Van Aalten, D.M.F. (登録日: 2003-08-01, 公開日: 2004-07-29, 最終更新日: 2023-12-13)

主引用文献

Komander, D.,Kular, G.S.,Bain, J.,Elliot, M.,Alessi, D.R.,Van Aalten, D.M.F.
Structural Basis for Ucn-01 (7-Hydroxystaurosporine) Specificity and Pdk1 (3-Phosphoinositide-Dependent Protein Kinase-1) Inhibition
Biochem.J., 375:255-, 2003

PubMed Abstract: PDK1 (3-phosphoinositide-dependent protein kinase-1) is a member of the AGC (cAMP-dependent, cGMP-dependent, protein kinase C) family of protein kinases, and has a key role in insulin and growth-factor signalling through phosphorylation and subsequent activation of a number of other AGC kinase family members, such as protein kinase B. The staurosporine derivative UCN-01 (7-hydroxystaurosporine) has been reported to be a potent inhibitor for PDK1, and is currently undergoing clinical trials for the treatment of cancer. Here, we report the crystal structures of staurosporine and UCN-01 in complex with the kinase domain of PDK1. We show that, although staurosporine and UCN-01 interact with the PDK1 active site in an overall similar manner, the UCN-01 7-hydroxy group, which is not present in staurosporine, generates direct and water-mediated hydrogen bonds with active-site residues. Inhibition data from UCN-01 tested against a panel of 29 different kinases show a different pattern of inhibition compared with staurosporine. We discuss how these differences in inhibition could be attributed to specific interactions with the additional 7-hydroxy group, as well as the size of the 7-hydroxy-group-binding pocket. This information could lead to opportunities for structure-based optimization of PDK1 inhibitors.

PubMed: 12892559
DOI: 10.1042/BJ20031119

実験手法

X-RAY DIFFRACTION (2.51 Å)