1okz

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[[Image:1okz.jpg|left|200px]]<br /><applet load="1okz" size="350" color="white" frame="true" align="right" spinBox="true"
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[[Image:1okz.jpg|left|200px]]
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caption="1okz, resolution 2.51&Aring;" />
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'''STRUCTURE OF HUMAN PDK1 KINASE DOMAIN IN COMPLEX WITH UCN-01'''<br />
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{{Structure
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|PDB= 1okz |SIZE=350|CAPTION= <scene name='initialview01'>1okz</scene>, resolution 2.51&Aring;
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|SITE= <scene name='pdbsite=BC3:Ucn+Binding+Site+For+Chain+A'>BC3</scene>
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|LIGAND= <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=UCN:7-HYDROXYSTAUROSPORINE'>UCN</scene> and <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>
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|ACTIVITY= [http://en.wikipedia.org/wiki/Transferred_entry:_2.7.11.1 Transferred entry: 2.7.11.1], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.37 2.7.1.37]
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|GENE=
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}}
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'''STRUCTURE OF HUMAN PDK1 KINASE DOMAIN IN COMPLEX WITH UCN-01'''
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==Overview==
==Overview==
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==About this Structure==
==About this Structure==
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1OKZ is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=SO4:'>SO4</scene>, <scene name='pdbligand=UCN:'>UCN</scene> and <scene name='pdbligand=GOL:'>GOL</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Transferred_entry:_2.7.11.1 Transferred entry: 2.7.11.1], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.37 2.7.1.37] Known structural/functional Site: <scene name='pdbsite=BC3:Ucn+Binding+Site+For+Chain+A'>BC3</scene>. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1OKZ OCA].
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1OKZ is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1OKZ OCA].
==Reference==
==Reference==
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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:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=12892559 12892559]
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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:[http://www.ncbi.nlm.nih.gov/pubmed/12892559 12892559]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Single protein]]
[[Category: Single protein]]
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[[Category: ucn-01]]
[[Category: ucn-01]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:18:53 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 13:12:19 2008''

Revision as of 11:12, 20 March 2008

Image:1okz.jpg


PDB ID 1okz

Drag the structure with the mouse to rotate
, resolution 2.51Å
Sites:
Ligands: , and
Activity: Transferred entry: 2.7.11.1, with EC number 2.7.1.37
Coordinates: save as pdb, mmCIF, xml



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

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