1uvr: Difference between revisions

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Revision as of 15:37, 20 March 2008

File:1uvr.jpg

, resolution 2.81Å

Sites:

Ligands:

, and

Activity:

Transferred entry: 2.7.11.1, with EC number 2.7.1.37

Coordinates:

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STRUCTURE OF HUMAN PDK1 KINASE DOMAIN IN COMPLEX WITH BIM-8

OverviewOverview

LY333531, BIM-1, BIM-2, BIM-3, and BIM-8 are bisindolyl maleimide-based, nanomolar protein kinase C inhibitors. LY333531, a PKCbeta-specific inhibitor, is in clinical trials against diabetes and cardiac ventricular hypertrophy complications. Specificity analysis with a panel of 29 protein kinases reveals that these bisindolyl maleimide inhibitors also inhibit PDK1, a key kinase from the insulin signaling pathway, albeit in the lower microM range. To understand the molecular basis of inhibition, the PDK1 kinase domain was cocrystallized with these bisindolyl maleimide inhibitors. The inhibitor complexes represent the first structural description of this class of compounds, revealing their unusual nonplanar conformation within the ATP binding site and also explaining the higher inhibitory potential of LY33331 compared to the BIM compounds toward PDK1. A combination of site-directed mutagenesis and essential dynamics analysis gives further insight into PDK1 and also PKC inhibition by these compounds, and may aid inhibitor design.

About this StructureAbout this Structure

1UVR is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

ReferenceReference

Interactions of LY333531 and other bisindolyl maleimide inhibitors with PDK1., Komander D, Kular GS, Schuttelkopf AW, Deak M, Prakash KR, Bain J, Elliott M, Garrido-Franco M, Kozikowski AP, Alessi DR, van Aalten DM, Structure. 2004 Feb;12(2):215-26. PMID:14962382

Page seeded by OCA on Thu Mar 20 14:37:25 2008

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OCA

@@ Line 1: / Line 1: @@
-[[Image:1uvr.jpg|left|200px]]<br /><applet load="1uvr" size="350" color="white" frame="true" align="right" spinBox="true"
+[[Image:1uvr.jpg|left|200px]]
-caption="1uvr, resolution 2.81&Aring;" />
-'''STRUCTURE OF HUMAN PDK1 KINASE DOMAIN IN COMPLEX WITH BIM-8'''<br />
+ {{Structure
+|PDB= 1uvr |SIZE=350|CAPTION= <scene name='initialview01'>1uvr</scene>, resolution 2.81&Aring;
+|SITE= <scene name='pdbsite=AC1:Bi8+Binding+Site+For+Chain+A'>AC1</scene>
+|LIGAND= <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=BI8:3-[1-(3-AMINOPROPYL)-1H-INDOL-3-YL]-4-(1-METHYL-1H-INDOL-3-YL)-1H-PYRROLE-2,5-DIONE'>BI8</scene> and <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>
+|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]
+|GENE=
+}}
+'''STRUCTURE OF HUMAN PDK1 KINASE DOMAIN IN COMPLEX WITH BIM-8'''
 ==Overview==
@@ Line 7: / Line 16: @@
 ==About this Structure==
-UVR 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=BI8:'>BI8</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=AC1:Bi8+Binding+Site+For+Chain+A'>AC1</scene>. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1UVR OCA].
+UVR 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=1UVR OCA].
 ==Reference==
-Interactions of LY333531 and other bisindolyl maleimide inhibitors with PDK1., Komander D, Kular GS, Schuttelkopf AW, Deak M, Prakash KR, Bain J, Elliott M, Garrido-Franco M, Kozikowski AP, Alessi DR, van Aalten DM, Structure. 2004 Feb;12(2):215-26. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=14962382 14962382]
+Interactions of LY333531 and other bisindolyl maleimide inhibitors with PDK1., Komander D, Kular GS, Schuttelkopf AW, Deak M, Prakash KR, Bain J, Elliott M, Garrido-Franco M, Kozikowski AP, Alessi DR, van Aalten DM, Structure. 2004 Feb;12(2):215-26. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/14962382 14962382]
 [[Category: Homo sapiens]]
 [[Category: Single protein]]
@@ Line 39: / Line 48: @@
 [[Category: transferase]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:28:49 2008''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 14:37:25 2008''