1OKZ

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

Summary for 1OKZ

• Entry DOI: 10.2210/pdb1okz/pdb
• Related: 1H1W 1OKY 1UU3 1UU7 1UU8 1UU9 1UVR
• Descriptor: 3-PHOSPHOINOSITIDE DEPENDENT PROTEIN KINASE 1, GLYCEROL, SULFATE ION, ... (5 entities in total)
• Functional Keywords: protein kinase, pkb, pdk1, ucn-01, 7-hydroxy staurosporine, inhibitor, transferase, atp-binding, phosphorylation
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 1
• Total formula weight: 37014.10

Authors

Komander, D.,Kular, G.S.,Alessi, D.R.,Van Aalten, D.M.F. (deposition date: 2003-08-01, release date: 2004-07-29, Last modification date: 2023-12-13)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.51 Å)