2y3a
From Proteopedia
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| - | [[Image:2y3a.png|left|200px]] | ||
| - | + | ==Crystal structure of p110beta in complex with icSH2 of p85beta and the drug GDC-0941== | |
| + | <StructureSection load='2y3a' size='340' side='right'caption='[[2y3a]], [[Resolution|resolution]] 3.30Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[2y3a]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2Y3A OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2Y3A FirstGlance]. <br> | ||
| + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.3Å</td></tr> | ||
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GD9:2-(1H-INDAZOL-4-YL)-6-{[4-(METHYLSULFONYL)PIPERAZIN-1-YL]METHYL}-4-MORPHOLIN-4-YL-THIENO[3,2-D]PYRIMIDINE'>GD9</scene></td></tr> | ||
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2y3a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2y3a OCA], [https://pdbe.org/2y3a PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2y3a RCSB], [https://www.ebi.ac.uk/pdbsum/2y3a PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2y3a ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/PK3CB_MOUSE PK3CB_MOUSE] Phosphoinositide-3-kinase (PI3K) that phosphorylates PtdIns (Phosphatidylinositol), PtdIns4P (Phosphatidylinositol 4-phosphate) and 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. Involved in the activation of AKT1 upon stimulation by G-protein coupled receptors (GPCRs) ligands such as CXCL12, sphingosine 1-phosphate, and lysophosphatidic acid. May also act downstream receptor tyrosine kinases. Required in different signaling pathways for stable platelet adhesion and aggregation. Plays a role in platelet activation signaling triggered by GPCRs, alpha-IIb/beta-3 integrins (ITGA2B/ ITGB3) and ITAM (immunoreceptor tyrosine-based activation motif)-bearing receptors such as GP6. Regulates the strength of adhesion of ITGA2B/ ITGB3 activated receptors necessary for the cellular transmission of contractile forces. Required for platelet aggregation induced by F2 (thrombin) and thromboxane A2 (TXA2). Has a role in cell survival. May have a role in cell migration. Involved in the early stage of autophagosome formation. Modulates the intracellular level of PtdIns3P (Phosphatidylinositol 3-phosphate) and activates PIK3C3 kinase activity. May act as a scaffold, independently of its lipid kinase activity to positively regulate autophagy. May have a role in insulin signaling as scaffolding protein in which the lipid kinase activity is not required. May have a kinase-independent function in regulating cell proliferation and in clathrin-mediated endocytosis. Mediator of oncogenic signal in cell lines lacking PTEN. The lipid kinase activity is necessary for its role in oncogenic transformation. Required for the growth of ERBB2 and RAS driven tumors.<ref>PMID:18594509</ref> <ref>PMID:18544649</ref> <ref>PMID:19515725</ref> <ref>PMID:20065293</ref> <ref>PMID:19940148</ref> <ref>PMID:21059846</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Phosphoinositide 3-kinases (PI3Ks) are essential for cell growth, migration, and survival. The structure of a p110beta/p85beta complex identifies an inhibitory function for the C-terminal SH2 domain (cSH2) of the p85 regulatory subunit. Mutagenesis of a cSH2 contact residue activates downstream signaling in cells. This inhibitory contact ties up the C-terminal region of the p110beta catalytic subunit, which is essential for lipid kinase activity. In vitro, p110beta basal activity is tightly restrained by contacts with three p85 domains: the cSH2, nSH2, and iSH2. RTK phosphopeptides relieve inhibition by nSH2 and cSH2 using completely different mechanisms. The binding site for the RTK's pYXXM motif is exposed on the cSH2, requiring an extended RTK motif to reach and disrupt the inhibitory contact with p110beta. This contrasts with the nSH2 where the pY-binding site itself forms the inhibitory contact. This establishes an unusual mechanism by which p85 SH2 domains contribute to RTK signaling specificities. | ||
| - | + | Structure of Lipid Kinase p110beta/p85beta Elucidates an Unusual SH2-Domain-Mediated Inhibitory Mechanism.,Zhang X, Vadas O, Perisic O, Anderson KE, Clark J, Hawkins PT, Stephens LR, Williams RL Mol Cell. 2011 Mar 4;41(5):567-78. PMID:21362552<ref>PMID:21362552</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | + | </div> | |
| - | + | <div class="pdbe-citations 2y3a" style="background-color:#fffaf0;"></div> | |
| - | + | ||
==See Also== | ==See Also== | ||
| - | *[[Phosphoinositide 3- | + | *[[Phosphoinositide 3-kinase 3D structures|Phosphoinositide 3-kinase 3D structures]] |
| - | + | == References == | |
| - | + | <references/> | |
| - | == | + | __TOC__ |
| - | < | + | </StructureSection> |
| + | [[Category: Large Structures]] | ||
[[Category: Mus musculus]] | [[Category: Mus musculus]] | ||
| - | + | [[Category: Perisic O]] | |
| - | [[Category: Perisic | + | [[Category: Vadas O]] |
| - | [[Category: Vadas | + | [[Category: Williams RL]] |
| - | [[Category: Williams | + | [[Category: Zhang X]] |
| - | [[Category: Zhang | + | |
| - | + | ||
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Current revision
Crystal structure of p110beta in complex with icSH2 of p85beta and the drug GDC-0941
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