3ibe

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{{Seed}}
 
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[[Image:3ibe.jpg|left|200px]]
 
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==Crystal Structure of a Pyrazolopyrimidine Inhibitor Bound to PI3 Kinase Gamma==
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The line below this paragraph, containing "STRUCTURE_3ibe", creates the "Structure Box" on the page.
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<StructureSection load='3ibe' size='340' side='right'caption='[[3ibe]], [[Resolution|resolution]] 2.80&Aring;' scene=''>
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== Structural highlights ==
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or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
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<table><tr><td colspan='2'>[[3ibe]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3IBE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3IBE FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.798&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=L64:1-(4-{4-MORPHOLIN-4-YL-1-[1-(PYRIDIN-3-YLCARBONYL)PIPERIDIN-4-YL]-1H-PYRAZOLO[3,4-D]PYRIMIDIN-6-YL}PHENYL)-3-PYRIDIN-4-YLUREA'>L64</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
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{{STRUCTURE_3ibe| PDB=3ibe | SCENE= }}
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3ibe FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ibe OCA], [https://pdbe.org/3ibe PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3ibe RCSB], [https://www.ebi.ac.uk/pdbsum/3ibe PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3ibe ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/PK3CG_HUMAN PK3CG_HUMAN] 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. Together with PIK3CD is involved in natural killer (NK) cell development and migration towards the sites of inflammation. Participates in T-lymphocyte migration. Regulates T-lymphocyte proliferation and cytokine production. Together with PIK3CD participates in T-lymphocyte development. Required for B-lymphocyte development and signaling. Together with PIK3CD participates in neutrophil respiratory burst. Together with PIK3CD is involved in neutrophil chemotaxis and 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. Contributes 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.<ref>PMID:7624799</ref> <ref>PMID:12163475</ref> <ref>PMID:15294162</ref> <ref>PMID:16094730</ref> <ref>PMID:21393242</ref>
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ib/3ibe_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</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=3ibe ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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The mammalian target of rapamycin (mTOR), a central regulator of growth, survival, and metabolism, is a validated target for cancer therapy. Rapamycin and its analogues, allosteric inhibitors of mTOR, only partially inhibit one mTOR protein complex. ATP-competitive, global inhibitors of mTOR that have the potential for enhanced anticancer efficacy are described. Structural features leading to potency and selectivity were identified and refined leading to compounds with in vivo efficacy in tumor xenograft models.
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===Crystal Structure of a Pyrazolopyrimidine Inhibitor Bound to PI3 Kinase Gamma===
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ATP-Competitive Inhibitors of the Mammalian Target of Rapamycin: Design and Synthesis of Highly Potent and Selective Pyrazolopyrimidines.,Zask A, Verheijen JC, Curran K, Kaplan J, Richard DJ, Nowak P, Malwitz DJ, Brooijmans N, Bard J, Svenson K, Lucas J, Toral-Barza L, Zhang WG, Hollander I, Gibbons JJ, Abraham RT, Ayral-Kaloustian S, Mansour TS, Yu K J Med Chem. 2009 Jul 31. PMID:19645448<ref>PMID:19645448</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 3ibe" style="background-color:#fffaf0;"></div>
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==See Also==
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The line below this paragraph, {{ABSTRACT_PUBMED_19645448}}, adds the Publication Abstract to the page
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*[[Phosphoinositide 3-kinase 3D structures|Phosphoinositide 3-kinase 3D structures]]
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(as it appears on PubMed at http://www.pubmed.gov), where 19645448 is the PubMed ID number.
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== References ==
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<references/>
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{{ABSTRACT_PUBMED_19645448}}
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__TOC__
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</StructureSection>
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==About this Structure==
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3IBE is a 1 chain 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=3IBE OCA].
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==Reference==
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<ref group="xtra">PMID:19645448</ref><references group="xtra"/>
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[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Phosphatidylinositol-4,5-bisphosphate 3-kinase]]
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[[Category: Large Structures]]
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[[Category: Bard, J.]]
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[[Category: Bard J]]
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[[Category: Svenson, K.]]
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[[Category: Svenson K]]
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[[Category: Atp-binding]]
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[[Category: Kinase]]
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[[Category: Nucleotide-binding]]
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[[Category: Pi3kinase inhibitor]]
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[[Category: Transferase]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Sep 3 15:36:22 2009''
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Current revision

Crystal Structure of a Pyrazolopyrimidine Inhibitor Bound to PI3 Kinase Gamma

PDB ID 3ibe

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