8dp0
From Proteopedia
(Difference between revisions)
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| - | '''Unreleased structure''' | ||
| - | + | ==Structure of p110 gamma bound to the Ras inhibitory nanobody NB7== | |
| + | <StructureSection load='8dp0' size='340' side='right'caption='[[8dp0]], [[Resolution|resolution]] 2.96Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[8dp0]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Lama_glama Lama glama]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8DP0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8DP0 FirstGlance]. <br> | ||
| + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 2.96Å</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=8dp0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8dp0 OCA], [https://pdbe.org/8dp0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8dp0 RCSB], [https://www.ebi.ac.uk/pdbsum/8dp0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8dp0 ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [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> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | PI3Kgamma is a critical immune signaling enzyme activated downstream of diverse cell surface molecules, including Ras, PKCbeta activated by the IgE receptor, and Gbetagamma subunits released from activated GPCRs. PI3Kgamma can form two distinct complexes, with the p110gamma catalytic subunit binding to either a p101 or p84 regulatory subunit, with these complexes being differentially activated by upstream stimuli. Here, using a combination of cryo electron microscopy, HDX-MS, and biochemical assays, we have identified novel roles of the helical domain of p110gamma in regulating lipid kinase activity of distinct PI3Kgamma complexes. We defined the molecular basis for how an allosteric inhibitory nanobody potently inhibits kinase activity through rigidifying the helical domain and regulatory motif of the kinase domain. The nanobody did not block either p110gamma membrane recruitment or Ras/Gbetagamma binding, but instead decreased ATP turnover. We also identified that p110gamma can be activated by dual PKCbeta helical domain phosphorylation leading to partial unfolding of an N-terminal region of the helical domain. PKCbeta phosphorylation is selective for p110gamma-p84 compared to p110gamma-p101, driven by differential dynamics of the helical domain of these different complexes. Nanobody binding prevented PKCbeta-mediated phosphorylation. Overall, this work shows an unexpected allosteric regulatory role of the helical domain of p110gamma that is distinct between p110gamma-p84 and p110gamma-p101 and reveals how this can be modulated by either phosphorylation or allosteric inhibitory binding partners. This opens possibilities of future allosteric inhibitor development for therapeutic intervention. | ||
| - | + | Allosteric activation or inhibition of PI3Kgamma mediated through conformational changes in the p110gamma helical domain.,Harris NJ, Jenkins ML, Nam SE, Rathinaswamy MK, Parson MAH, Ranga-Prasad H, Dalwadi U, Moeller BE, Sheeky E, Hansen SD, Yip CK, Burke JE Elife. 2023 Jul 7;12:RP88058. doi: 10.7554/eLife.88058. PMID:37417733<ref>PMID:37417733</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| + | <div class="pdbe-citations 8dp0" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
| + | [[Category: Lama glama]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Burke JE]] | ||
| + | [[Category: Nam SE]] | ||
| + | [[Category: Rathinaswamy MK]] | ||
| + | [[Category: Yip CK]] | ||
Revision as of 06:12, 19 July 2023
Structure of p110 gamma bound to the Ras inhibitory nanobody NB7
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