1oky
From Proteopedia
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==Overview== | ==Overview== | ||
| - | PDK1 (3-phosphoinositide-dependent protein kinase-1) is a member of the | + | 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== | ==About this Structure== | ||
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[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Transferred entry: 2 | + | [[Category: Transferred entry: 2 7.11 1]] |
| - | [[Category: Aalten, D | + | [[Category: Aalten, D M.F Van.]] |
| - | [[Category: Alessi, D | + | [[Category: Alessi, D R.]] |
[[Category: Komander, D.]] | [[Category: Komander, D.]] | ||
| - | [[Category: Kular, G | + | [[Category: Kular, G S.]] |
[[Category: GOL]] | [[Category: GOL]] | ||
[[Category: SO4]] | [[Category: SO4]] | ||
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[[Category: transferase]] | [[Category: transferase]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:18:53 2008'' |
Revision as of 12:18, 21 February 2008
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STRUCTURE OF HUMAN PDK1 KINASE DOMAIN IN COMPLEX WITH STAUROSPORINE
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
1OKY is a Single protein structure of sequence from Homo sapiens with , and as ligands. Active as Transferred entry: 2.7.11.1, with EC number 2.7.1.37 Known structural/functional Site: . 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 Thu Feb 21 14:18:53 2008
Categories: Homo sapiens | Single protein | Transferred entry: 2 7.11 1 | Aalten, D M.F Van. | Alessi, D R. | Komander, D. | Kular, G S. | GOL | SO4 | STU | Pdk1 | Pkb | Protein kinase | Staurosporine | Transferase
