This old version of Proteopedia is provided for student assignments while the new version is undergoing repairs. Content and edits done in this old version of Proteopedia after March 1, 2026 will eventually be lost when it is retired in about June of 2026.

Apply for new accounts at the new Proteopedia. Your logins will work in both the old and new versions.

6c1s

From Proteopedia

(Difference between revisions)

Jump to: navigation, search

Revision as of 06:12, 11 July 2018

Phosphoinositide 3-Kinase gamma bound to an pyrrolopyridinone Inhibitor

Structural highlights

6c1s is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Gene:	PIK3CG (HUMAN)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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 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^[6]

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

References

↑ Stoyanov B, Volinia S, Hanck T, Rubio I, Loubtchenkov M, Malek D, Stoyanova S, Vanhaesebroeck B, Dhand R, Nurnberg B, et al.. Cloning and characterization of a G protein-activated human phosphoinositide-3 kinase. Science. 1995 Aug 4;269(5224):690-3. PMID:7624799
↑ Naga Prasad SV, Laporte SA, Chamberlain D, Caron MG, Barak L, Rockman HA. Phosphoinositide 3-kinase regulates beta2-adrenergic receptor endocytosis by AP-2 recruitment to the receptor/beta-arrestin complex. J Cell Biol. 2002 Aug 5;158(3):563-75. Epub 2002 Aug 5. PMID:12163475 doi:10.1083/jcb.200202113
↑ Patrucco E, Notte A, Barberis L, Selvetella G, Maffei A, Brancaccio M, Marengo S, Russo G, Azzolino O, Rybalkin SD, Silengo L, Altruda F, Wetzker R, Wymann MP, Lembo G, Hirsch E. PI3Kgamma modulates the cardiac response to chronic pressure overload by distinct kinase-dependent and -independent effects. Cell. 2004 Aug 6;118(3):375-87. PMID:15294162 doi:10.1016/j.cell.2004.07.017
↑ Naga Prasad SV, Jayatilleke A, Madamanchi A, Rockman HA. Protein kinase activity of phosphoinositide 3-kinase regulates beta-adrenergic receptor endocytosis. Nat Cell Biol. 2005 Aug;7(8):785-96. PMID:16094730
↑ Wilson LS, Baillie GS, Pritchard LM, Umana B, Terrin A, Zaccolo M, Houslay MD, Maurice DH. A phosphodiesterase 3B-based signaling complex integrates exchange protein activated by cAMP 1 and phosphatidylinositol 3-kinase signals in human arterial endothelial cells. J Biol Chem. 2011 May 6;286(18):16285-96. doi: 10.1074/jbc.M110.217026. Epub 2011, Mar 10. PMID:21393242 doi:10.1074/jbc.M110.217026
↑ 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. 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). J Med Chem. 2018 Jun 14. doi: 10.1021/acs.jmedchem.8b00085. PMID:29847724 doi:http://dx.doi.org/10.1021/acs.jmedchem.8b00085

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6c1s"

@@ Line 3: / Line 3: @@
 <StructureSection load='6c1s' size='340' side='right' caption='[[6c1s]], [[Resolution|resolution]] 2.31&Aring;' 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>
+<table><tr><td colspan='2'>[[6c1s]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. 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='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PIK3CG ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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>
@@ Line 22: / Line 23: @@
 __TOC__
 </StructureSection>
+[[Category: Human]]
 [[Category: Griffin, J P]]
 [[Category: Jacobs, M D]]

6c1s

From Proteopedia

Revision as of 06:12, 11 July 2018

Phosphoinositide 3-Kinase gamma bound to an pyrrolopyridinone Inhibitor

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

Personal tools

Navigation

Search

Toolbox