| Structural highlights
4anu 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: | , |
| Related: | 1e8y, 1e8z, 1he8, 2a4z, 2a5u, 2chw, 2chx, 2chz, 2v4l, 3zvv, 3zw3, 4anv, 4anw, 4anx |
| 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 phosphoinositide 3-kinases (PI3Ks) have been linked to an extraordinarily diversified group of cellular functions making these enzymes compelling targets for the treatment of disease. A large body of evidence has linked PI3Kgamma to the modulation of autoimmune and inflammatory processes making it an intriguing target for drug discovery. Our high-throughput screening (HTS) campaign revealed two hits that were nominated for further optimization studies. The in vitro activity of the first HTS hit, designated as the sulfonylpiperazine scaffold, was optimized utilizing structure-based design. However, nonoptimal pharmacokinetic properties precluded this series from further studies. An overlay of the X-ray structures of the sulfonylpiperazine scaffold and the second HTS hit within their complexes with PI3Kgamma revealed a high degree of overlap. This feature was utilized to design a series of hybrid analogues including advanced leads such as 31 with desirable potency, selectivity, and oral bioavailability.
Discovery of a Novel Series of Potent and Orally Bioavailable Phosphoinositide 3-Kinase gamma Inhibitors.,Leahy JW, Buhr CA, Johnson HW, Kim BG, Baik T, Cannoy J, Forsyth TP, Jeong JW, Lee MS, Ma S, Noson K, Wang L, Williams M, Nuss JM, Brooks E, Foster P, Goon L, Heald N, Holst C, Jaeger C, Lam S, Lougheed J, Nguyen L, Plonowski A, Song J, Stout T, Wu X, Yakes MF, Yu P, Zhang W, Lamb P, Raeber O J Med Chem. 2012 May 17. PMID:22548342[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
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
- ↑ Leahy JW, Buhr CA, Johnson HW, Kim BG, Baik T, Cannoy J, Forsyth TP, Jeong JW, Lee MS, Ma S, Noson K, Wang L, Williams M, Nuss JM, Brooks E, Foster P, Goon L, Heald N, Holst C, Jaeger C, Lam S, Lougheed J, Nguyen L, Plonowski A, Song J, Stout T, Wu X, Yakes MF, Yu P, Zhang W, Lamb P, Raeber O. Discovery of a Novel Series of Potent and Orally Bioavailable Phosphoinositide 3-Kinase gamma Inhibitors. J Med Chem. 2012 May 17. PMID:22548342 doi:10.1021/jm300403a
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