1e7u: Difference between revisions

Revision as of 14:46, 2 May 2008

STRUCTURE DETERMINANTS OF PHOSPHOINOSITIDE 3-KINASE INHIBITION BY WORTMANNIN, LY294002, QUERCETIN, MYRICETIN AND STAUROSPORINE

OverviewOverview

The specific phosphoinositide 3-kinase (PI3K) inhibitors wortmannin and LY294002 have been invaluable tools for elucidating the roles of these enzymes in signal transduction pathways. The X-ray crystallographic structures of PI3Kgamma bound to these lipid kinase inhibitors and to the broad-spectrum protein kinase inhibitors quercetin, myricetin, and staurosporine reveal how these compounds fit into the ATP binding pocket. With a nanomolar IC50, wortmannin most closely fits and fills the active site and induces a conformational change in the catalytic domain. Surprisingly, LY294002 and the lead compound on which it was designed, quercetin, as well as the closely related flavonoid myricetin bind PI3K in remarkably different orientations that are related to each other by 180 degrees rotations. Staurosporine/PI3K interactions are reminiscent of low-affinity protein kinase/staurosporine complexes. These results provide a rich basis for development of isoform-specific PI3K inhibitors with therapeutic potential.

About this StructureAbout this Structure

1E7U is a Single protein structure of sequence from Sus scrofa. Full crystallographic information is available from OCA.

ReferenceReference

Structural determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin, and staurosporine., Walker EH, Pacold ME, Perisic O, Stephens L, Hawkins PT, Wymann MP, Williams RL, Mol Cell. 2000 Oct;6(4):909-19. PMID:11090628 Page seeded by OCA on Fri May 2 14:46:18 2008

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

OCA

@@ Line 1: / Line 1: @@
 [[Image:1e7u.gif|left|200px]]
- {{Structure
+<!--
-|PDB= 1e7u |SIZE=350|CAPTION= <scene name='initialview01'>1e7u</scene>, resolution 2.0&Aring;
+The line below this paragraph, containing "STRUCTURE_1e7u", creates the "Structure Box" on the page.
-|SITE= <scene name='pdbsite=KWT:Site+Of+Covalent+Attachment+Of+Wortmannin+To+Protein'>KWT</scene>
+You may change the PDB parameter (which sets the PDB file loaded into the applet)
-|LIGAND= <scene name='pdbligand=KWT:(1S,6BR,9AS,11R,11BR)-9A,11B-DIMETHYL-1-[(METHYLOXY)METHYL]-3,6,9-TRIOXO-1,6,6B,7,8,9,9A,10,11,11B-DECAHYDRO-3H-FURO[4,3,2-DE]INDENO[4,5-H][2]BENZOPYRAN-11-YL+ACETATE'>KWT</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/Phosphatidylinositol_3-kinase Phosphatidylinositol 3-kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.137 2.7.1.137] </span>
+or leave the SCENE parameter empty for the default display.
-|GENE= P120S144C ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9823 Sus scrofa])
+-->
-|DOMAIN=
+{{STRUCTURE_1e7u|  PDB=1e7u  |  SCENE=  }}
-|RELATEDENTRY=
-|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1e7u FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1e7u OCA], [http://www.ebi.ac.uk/pdbsum/1e7u PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1e7u RCSB]</span>
-}}
 '''STRUCTURE DETERMINANTS OF PHOSPHOINOSITIDE 3-KINASE INHIBITION BY WORTMANNIN, LY294002, QUERCETIN, MYRICETIN AND STAUROSPORINE'''
@@ Line 31: / Line 28: @@
 [[Category: Walker, E H.]]
 [[Category: Williams, R L.]]
-[[Category: phosphoinositide 3-kinase gamma]]
+[[Category: Phosphoinositide 3-kinase gamma]]
-[[Category: pi 3k]]
+[[Category: Pi 3k]]
-[[Category: pi3k]]
+[[Category: Pi3k]]
-[[Category: secondary messenger generation]]
+[[Category: Secondary messenger generation]]
-[[Category: wortmannin]]
+[[Category: Wortmannin]]
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri May  2 14:46:18 2008''
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Mar 30 19:57:01 2008''