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1okz

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{{STRUCTURE_1okz| PDB=1okz | SCENE= }}
{{STRUCTURE_1okz| PDB=1okz | SCENE= }}
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'''STRUCTURE OF HUMAN PDK1 KINASE DOMAIN IN COMPLEX WITH UCN-01'''
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===STRUCTURE OF HUMAN PDK1 KINASE DOMAIN IN COMPLEX WITH UCN-01===
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==Overview==
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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.
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==About this Structure==
==About this Structure==
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[[Category: Transferase]]
[[Category: Transferase]]
[[Category: Ucn-01]]
[[Category: Ucn-01]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 03:59:02 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 29 02:29:20 2008''

Revision as of 23:29, 28 July 2008

Image:1okz.png

Template:STRUCTURE 1okz

STRUCTURE OF HUMAN PDK1 KINASE DOMAIN IN COMPLEX WITH UCN-01

Template:ABSTRACT PUBMED 12892559

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

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