6c1s: Difference between revisions
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==Phosphoinositide 3-Kinase gamma bound to an pyrrolopyridinone Inhibitor== | |||
<StructureSection load='6c1s' size='340' side='right' caption='[[6c1s]], [[Resolution|resolution]] 2.31Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6c1s]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6C1S OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6C1S FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EFV:{4-[2-(5,6-dimethoxypyridin-3-yl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-1H-pyrazol-1-yl}acetonitrile'>EFV</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></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=6c1s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6c1s OCA], [http://pdbe.org/6c1s PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6c1s RCSB], [http://www.ebi.ac.uk/pdbsum/6c1s PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6c1s ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[[http://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 == | |||
The lipid kinase phosphoinositide 3-kinase gamma (PI3Kgamma) has attracted attention as a potential target to treat a variety of autoimmune disorders, including multiple sclerosis, due to its role in immune modulation and microglial activation. By minimizing the number of hydrogen bond donors while targeting a previously uncovered selectivity pocket adjacent to the ATP binding site of PI3Kgamma, we discovered a series of azaisoindolinones as selective, brain penetrant inhibitors of PI3Kgamma. This ultimately led to the discovery of 16, an orally bioavailable compound that showed efficacy in murine experimental autoimmune encephalomyelitis (EAE), a preclinical model of multiple sclerosis. | |||
Design and Synthesis of a Novel Series of Orally Bioavailable, CNS-Penetrant, Isoform Selective Phosphoinositide 3-Kinase gamma (PI3Kgamma) Inhibitors with Potential for the Treatment of Multiple Sclerosis (MS).,Come JH, Collier PN, Henderson JA, Pierce AC, Davies RJ, Le Tiran A, O'Dowd H, Bandarage UK, Cao J, Deininger D, Grey R, Krueger EB, Lowe DB, Liang J, Liao Y, Messersmith D, Nanthakumar S, Sizensky E, Wang J, Xu J, Chin EY, Damagnez V, Doran JD, Dworakowski W, Griffith JP, Jacobs MD, Khare-Pandit S, Mahajan S, Moody CS, Aronov AM J Med Chem. 2018 Jun 14. doi: 10.1021/acs.jmedchem.8b00085. PMID:29847724<ref>PMID:29847724</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
[[Category: Griffin, J | <div class="pdbe-citations 6c1s" style="background-color:#fffaf0;"></div> | ||
[[Category: Jacobs, M | == References == | ||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Griffin, J P]] | |||
[[Category: Jacobs, M D]] | |||
[[Category: Inhibitor]] | |||
[[Category: Kinase]] | |||
[[Category: Transferase-transferase inhibitor complex]] | |||
Revision as of 08:35, 27 June 2018
Phosphoinositide 3-Kinase gamma bound to an pyrrolopyridinone InhibitorPhosphoinositide 3-Kinase gamma bound to an pyrrolopyridinone Inhibitor
Structural highlights
Function[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.[1] [2] [3] [4] [5] Publication Abstract from PubMedThe lipid kinase phosphoinositide 3-kinase gamma (PI3Kgamma) has attracted attention as a potential target to treat a variety of autoimmune disorders, including multiple sclerosis, due to its role in immune modulation and microglial activation. By minimizing the number of hydrogen bond donors while targeting a previously uncovered selectivity pocket adjacent to the ATP binding site of PI3Kgamma, we discovered a series of azaisoindolinones as selective, brain penetrant inhibitors of PI3Kgamma. This ultimately led to the discovery of 16, an orally bioavailable compound that showed efficacy in murine experimental autoimmune encephalomyelitis (EAE), a preclinical model of multiple sclerosis. Design and Synthesis of a Novel Series of Orally Bioavailable, CNS-Penetrant, Isoform Selective Phosphoinositide 3-Kinase gamma (PI3Kgamma) Inhibitors with Potential for the Treatment of Multiple Sclerosis (MS).,Come JH, Collier PN, Henderson JA, Pierce AC, Davies RJ, Le Tiran A, O'Dowd H, Bandarage UK, Cao J, Deininger D, Grey R, Krueger EB, Lowe DB, Liang J, Liao Y, Messersmith D, Nanthakumar S, Sizensky E, Wang J, Xu J, Chin EY, Damagnez V, Doran JD, Dworakowski W, Griffith JP, Jacobs MD, Khare-Pandit S, Mahajan S, Moody CS, Aronov AM J Med Chem. 2018 Jun 14. doi: 10.1021/acs.jmedchem.8b00085. PMID:29847724[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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