1okz
From Proteopedia
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'''STRUCTURE OF HUMAN PDK1 KINASE DOMAIN IN COMPLEX WITH UCN-01''' | '''STRUCTURE OF HUMAN PDK1 KINASE DOMAIN IN COMPLEX WITH UCN-01''' | ||
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[[Category: Kular, G S.]] | [[Category: Kular, G S.]] | ||
[[Category: 7-hydroxy staurosporine]] | [[Category: 7-hydroxy staurosporine]] | ||
| - | [[Category: | + | [[Category: Atp-binding]] |
| - | [[Category: | + | [[Category: Inhibitor]] |
| - | [[Category: | + | [[Category: Pdk1]] |
| - | [[Category: | + | [[Category: Phosphorylation]] |
| - | [[Category: | + | [[Category: Pkb]] |
| - | [[Category: | + | [[Category: Protein kinase]] |
| - | [[Category: | + | [[Category: Transferase]] |
| - | [[Category: | + | [[Category: Ucn-01]] |
| - | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 03:59:02 2008'' | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | |
Revision as of 00:59, 3 May 2008
STRUCTURE OF HUMAN PDK1 KINASE DOMAIN IN COMPLEX WITH UCN-01
Overview
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.
About this Structure
1OKZ is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Structural basis for UCN-01 (7-hydroxystaurosporine) specificity and PDK1 (3-phosphoinositide-dependent protein kinase-1) inhibition., Komander D, Kular GS, Bain J, Elliott M, Alessi DR, Van Aalten DM, Biochem J. 2003 Oct 15;375(Pt 2):255-62. PMID:12892559 Page seeded by OCA on Sat May 3 03:59:02 2008
