1uu3: Difference between revisions

Revision as of 11:41, 3 May 2008

STRUCTURE OF HUMAN PDK1 KINASE DOMAIN IN COMPLEX WITH LY333531

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

1UU3 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 Sat May 3 11:41:33 2008

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA

@@ Line 1: / Line 1: @@
 [[Image:1uu3.jpg|left|200px]]
- {{Structure
+<!--
-|PDB= 1uu3 |SIZE=350|CAPTION= <scene name='initialview01'>1uu3</scene>, resolution 1.70&Aring;
+The line below this paragraph, containing "STRUCTURE_1uu3", creates the "Structure Box" on the page.
-|SITE= <scene name='pdbsite=AC1:Ly4+Binding+Site+For+Chain+A'>AC1</scene>
+You may change the PDB parameter (which sets the PDB file loaded into the applet)
-|LIGAND= <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=LY4:(9R)-9-[(DIMETHYLAMINO)METHYL]-6,7,10,11-TETRAHYDRO-9H,18H-5,21&#58;12,17-DIMETHENODIBENZO[E,K]PYRROLO[3,4-H][1,4,13]OXADIAZACYCLOHEXADECINE-18,20-DIONE'>LY4</scene>, <scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>
+or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
-|ACTIVITY= <span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </span>
+or leave the SCENE parameter empty for the default display.
-|GENE=
+-->
-|DOMAIN=
+{{STRUCTURE_1uu3|  PDB=1uu3  |  SCENE=  }}
-|RELATEDENTRY=
-|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1uu3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1uu3 OCA], [http://www.ebi.ac.uk/pdbsum/1uu3 PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1uu3 RCSB]</span>
-}}
 '''STRUCTURE OF HUMAN PDK1 KINASE DOMAIN IN COMPLEX WITH LY333531'''
@@ Line 37: / Line 34: @@
 [[Category: Prakash, K R.]]
 [[Category: Schuttelkopf, A W.]]
-[[Category: cancer]]
+[[Category: Cancer]]
-[[Category: diabetes]]
+[[Category: Diabetes]]
-[[Category: inhibitor]]
+[[Category: Inhibitor]]
-[[Category: ly333531]]
+[[Category: Ly333531]]
-[[Category: pdk1]]
+[[Category: Pdk1]]
-[[Category: pkb]]
+[[Category: Pkb]]
-[[Category: protein kinase]]
+[[Category: Protein kinase]]
-[[Category: serine/threonine-protein kinase]]
+[[Category: Serine/threonine-protein kinase]]
-[[Category: transferase]]
+[[Category: Transferase]]
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May  3 11:41:33 2008''
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 00:15:16 2008''