1e8w

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(Difference between revisions)

Revision as of 04:00, 6 September 2017

Structure determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin and staurosporine

Structural highlights

1e8w is a 1 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Related:	1e7u, 1e7v, 1e8x, 1qmm
Activity:	Phosphatidylinositol 3-kinase, with EC number 2.7.1.137
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[PK3CG_PIG] Phosphoinositide-3-kinase (PI3K) that phosphorylates PtdIns(4,5)P2 (Phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Links G-protein coupled receptor activation to PIP3 production. Involved in immune, inflammatory and allergic responses. Modulates leukocyte chemotaxis to inflammatory sites and in response to chemoattractant agents. May control leukocyte polarization and migration by regulating the spatial accumulation of PIP3 and by regulating the organization of F-actin formation and integrin-based adhesion at the leading edge. Controls motility of dendritic cells. Participates in T-lymphocyte migration. Regulates T-lymphocyte proliferation and cytokine production. Required for B-lymphocyte development and signaling. Together with other PI3Ks are involved in the oxidative burst produced by neutrophils in response to chemotactic agents. Together with PIK3CD regulate neutrophil extravasation. Together with PIK3CB promotes platelet aggregation and thrombosis. Regulates alpha-IIb/beta-3 integrins (ITGA2B/ ITGB3) adhesive function in platelets downstream of P2Y12 through a lipid kinase activity-independent mechanism. May have also a lipid kinase activity-dependent function in platelet aggregation. Involved in endothelial progenitor cell migration. Negative regulator of cardiac contractility. Modulates cardiac contractility by anchoring protein kinase A (PKA) and PDE3B activation, reducing cAMP levels. Regulates cardiac contractility also by promoting beta-adrenergic receptor internalization by binding to ADRBK1 and by non-muscle tropomyosin phosphorylation. Also has serine/threonine protein kinase activity: both lipid and protein kinase activities are required for beta-adrenergic receptor endocytosis. May also have a scaffolding role in modulating cardiac contractility. Contribute to cardiac hypertrophy under pathological stress. Through simultaneous binding of PDE3B to RAPGEF3 and PIK3R6 is assembled in a signaling complex in which the PI3K gamma complex is activated by RAPGEF3 and which is involved in angiogenesis (By similarity).

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

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.

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^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Walker EH, Pacold ME, Perisic O, Stephens L, Hawkins PT, Wymann MP, Williams RL. Structural determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin, and staurosporine. Mol Cell. 2000 Oct;6(4):909-19. PMID:11090628

1 Structural highlights
2 Function
3 Evolutionary Conservation
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/1e8w"

@@ Line 1: / Line 1: @@
-==STRUCTURE DETERMINANTS OF PHOSPHOINOSITIDE 3-KINASE INHIBITION BY WORTMANNIN, LY294002, QUERCETIN, MYRICETIN AND STAUROSPORINE==
+==Structure determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin and staurosporine==
 <StructureSection load='1e8w' size='340' side='right' caption='[[1e8w]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[1e8w]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Pig Pig]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1E8W OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1E8W FirstGlance]. <br>
+<table><tr><td colspan='2'>[[1e8w]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1E8W OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1E8W FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=QUE:3,5,7,3,4-PENTAHYDROXYFLAVONE'>QUE</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1e7u|1e7u]], [[1e7v|1e7v]], [[1e8x|1e8x]], [[1qmm|1qmm]]</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">P120S144C ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9823 PIG])</td></tr>
 <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><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></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1e8w FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1e8w OCA], [http://pdbe.org/1e8w PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1e8w RCSB], [http://www.ebi.ac.uk/pdbsum/1e8w PDBsum]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1e8w FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1e8w OCA], [http://pdbe.org/1e8w PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1e8w RCSB], [http://www.ebi.ac.uk/pdbsum/1e8w PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=1e8w ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 19: / Line 19: @@
     <text>to colour the structure by Evolutionary Conservation</text>
   </jmolCheckbox>
-</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf].
+</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1e8w ConSurf].
 <div style="clear:both"></div>
 <div style="background-color:#fffaf0;">
@@ Line 38: / Line 38: @@
 </StructureSection>
 [[Category: Phosphatidylinositol 3-kinase]]
-[[Category: Pig]]
 [[Category: Hawkins, P T]]
 [[Category: Pacold, M E]]

1e8w

From Proteopedia

Revision as of 04:00, 6 September 2017

Structure determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin and staurosporine

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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