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PDBsum entry 1e7u

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Phosphoinositide 3-kinase gamma PDB id
1e7u
Jmol
Contents
Protein chain
872 a.a. *
Ligands
KWT
Waters ×164
* Residue conservation analysis
PDB id:
1e7u
Name: Phosphoinositide 3-kinase gamma
Title: Structure determinants of phosphoinositide 3-kinase inhibition by wortmannin, ly294002, quercetin, myricetin and staurosporine
Structure: Phosphatidylinositol 3-kinase catalytic subunit. Chain: a. Fragment: pi3-kinase p110 subunit gamma. Synonym: ptdins-3-kinase p110, pi3k, pi 3k. Engineered: yes. Mutation: yes. Other_details: wortmannin
Source: Sus scrofa. Wild boar. Organism_taxid: 9823. Cell: neutrophil. Plasmid: pachlt-c. Gene: p120s144c. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.
Resolution:
2.0Å     R-factor:   0.254     R-free:   0.298
Authors: E.H.Walker,O.Perisic,C.Ried,L.Stephens,R.L.Williams
Key ref:
E.H.Walker et al. (2000). Structural determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin, and staurosporine. Mol Cell, 6, 909-919. PubMed id: 11090628 DOI: 10.1016/S1097-2765(05)00089-4
Date:
08-Sep-00     Release date:   17-Nov-00    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
O02697  (PK3CG_PIG) -  Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
Seq:
Struc:
 
Seq:
Struc:
 
Seq:
Struc:
1102 a.a.
872 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 4 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class 2: E.C.2.7.1.153  - Phosphatidylinositol-4,5-bisphosphate 3-kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

      Pathway:
1-Phosphatidyl-myo-inositol Metabolism
      Reaction: ATP + 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate = ADP + 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate
ATP
+ 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate
= ADP
+ 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate
   Enzyme class 3: E.C.2.7.11.1  - Non-specific serine/threonine protein kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + a protein = ADP + a phosphoprotein
ATP
+ protein
= ADP
+ phosphoprotein
Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     phosphatidylinositol-mediated signaling   2 terms 
  Biochemical function     transferase activity, transferring phosphorus-containing groups     2 terms  

 

 
    reference    
 
 
DOI no: 10.1016/S1097-2765(05)00089-4 Mol Cell 6:909-919 (2000)
PubMed id: 11090628  
 
 
Structural determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin, and staurosporine.
E.H.Walker, M.E.Pacold, O.Perisic, L.Stephens, P.T.Hawkins, M.P.Wymann, R.L.Williams.
 
  ABSTRACT  
 
The specific phosphoinositide 3-kinase (PI3K) inhibitors wortmannin and LY294002 have been invaluable tools for elucidating the roles of these enzymes in signal transduction pathways. The X-ray crystallographic structures of PI3Kgamma bound to these lipid kinase inhibitors and to the broad-spectrum protein kinase inhibitors quercetin, myricetin, and staurosporine reveal how these compounds fit into the ATP binding pocket. With a nanomolar IC50, wortmannin most closely fits and fills the active site and induces a conformational change in the catalytic domain. Surprisingly, LY294002 and the lead compound on which it was designed, quercetin, as well as the closely related flavonoid myricetin bind PI3K in remarkably different orientations that are related to each other by 180 degrees rotations. Staurosporine/PI3K interactions are reminiscent of low-affinity protein kinase/staurosporine complexes. These results provide a rich basis for development of isoform-specific PI3K inhibitors with therapeutic potential.
 
  Selected figure(s)  
 
Figure 4.
Figure 5.
Figure 5. Stereoplots of the Active Sites of the PI3K Inhibitor ComplexesHydrogen bonds are shown as red dotted lines. (A) ATP, (B) Wortmannin, (C) LY294002, (D) Quercetin, (E) Myricetin, (F) Staurosporine.
 
  The above figures are reprinted by permission from Cell Press: Mol Cell (2000, 6, 909-919) copyright 2000.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

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PDB codes: 2wxe 2wxf 2wxg 2wxh 2wxi 2wxj 2wxk 2wxl 2wxm 2wxn 2wxo 2wxp 2wxq 2wxr 2x38
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PDB codes: 3lj0 3lj1 3lj2
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Protein and lipid kinase inhibitors as targeted anticancer agents of the Ras/Raf/MEK and PI3K/PKB pathways.
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S9, a novel anticancer agent, exerts its anti-proliferative activity by interfering with both PI3K-Akt-mTOR signaling and microtubule cytoskeleton.
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A frequent kinase domain mutation that changes the interaction between PI3Kalpha and the membrane.
  Proc Natl Acad Sci U S A, 106, 16996-17001.
PDB codes: 3hhm 3hiz
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Akt inhibitor Akt-IV blocks virus replication through an Akt-independent mechanism.
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19568796 L.M.Ballou, and R.Z.Lin (2008).
Rapamycin and mTOR kinase inhibitors.
  J Chem Biol, 1, 27-36.  
18421779 L.Pirola, and S.Fröjdö (2008).
Resveratrol: one molecule, many targets.
  IUBMB Life, 60, 323-332.  
18489260 M.Frazzetto, C.Suphioglu, J.Zhu, O.Schmidt-Kittler, I.G.Jennings, S.L.Cranmer, S.P.Jackson, K.W.Kinzler, B.Vogelstein, and P.E.Thompson (2008).
Dissecting isoform selectivity of PI3K inhibitors: the role of non-conserved residues in the catalytic pocket.
  Biochem J, 414, 383-390.  
18591783 M.Nomura, T.Takahashi, N.Nagata, K.Tsutsumi, S.Kobayashi, T.Akiba, K.Yokogawa, S.Moritani, and K.Miyamoto (2008).
Inhibitory mechanisms of flavonoids on insulin-stimulated glucose uptake in MC3T3-G2/PA6 adipose cells.
  Biol Pharm Bull, 31, 1403-1409.  
18067462 N.Neznanov, A.Kondratova, K.M.Chumakov, L.Neznanova, R.Kondratov, A.K.Banerjee, and A.V.Gudkov (2008).
Quercetinase pirin makes poliovirus replication resistant to flavonoid quercetin.
  DNA Cell Biol, 27, 191-198.  
19568798 R.M.Gunn, and H.C.Hailes (2008).
Insights into the PI3-K-PKB-mTOR signalling pathway from small molecules.
  J Chem Biol, 1, 49-62.  
18184861 R.Zeng, Y.Yao, M.Han, X.Zhao, X.C.Liu, J.Wei, Y.Luo, J.Zhang, J.Zhou, S.Wang, D.Ma, and G.Xu (2008).
Biliverdin reductase mediates hypoxia-induced EMT via PI3-kinase and Akt.
  J Am Soc Nephrol, 19, 380-387.  
18791070 S.Gentile, N.Martin, E.Scappini, J.Williams, C.Erxleben, and D.L.Armstrong (2008).
The human ERG1 channel polymorphism, K897T, creates a phosphorylation site that inhibits channel activity.
  Proc Natl Acad Sci U S A, 105, 14704-14708.  
18208370 S.M.Maira, C.Voliva, and C.Garcia-Echeverria (2008).
Class IA phosphatidylinositol 3-kinase: from their biologic implication in human cancers to drug discovery.
  Expert Opin Ther Targets, 12, 223-238.  
18566477 T.A.Klink, K.M.Kleman-Leyer, A.Kopp, T.A.Westermeyer, and R.G.Lowery (2008).
Evaluating PI3 kinase isoforms using Transcreener ADP assays.
  J Biomol Screen, 13, 476-485.  
18794884 T.L.Yuan, and L.C.Cantley (2008).
PI3K pathway alterations in cancer: variations on a theme.
  Oncogene, 27, 5497-5510.  
18634052 Y.A.Wang, S.K.Johnson, B.L.Brown, L.M.McCarragher, K.Al-Sakkaf, J.A.Royds, and P.R.Dobson (2008).
Enhanced anti-cancer effect of a phosphatidylinositol-3 kinase inhibitor and doxorubicin on human breast epithelial cell lines with different p53 and oestrogen receptor status.
  Int J Cancer, 123, 1536-1544.  
19384426 A.Arcaro, and A.S.Guerreiro (2007).
The phosphoinositide 3-kinase pathway in human cancer: genetic alterations and therapeutic implications.
  Curr Genomics, 8, 271-306.  
18079394 C.H.Huang, D.Mandelker, O.Schmidt-Kittler, Y.Samuels, V.E.Velculescu, K.W.Kinzler, B.Vogelstein, S.B.Gabelli, and L.M.Amzel (2007).
The structure of a human p110alpha/p85alpha complex elucidates the effects of oncogenic PI3Kalpha mutations.
  Science, 318, 1744-1748.
PDB code: 2rd0
17237296 D.Kessel, J.J.Reiners, S.T.Hazeldine, L.Polin, and J.P.Horwitz (2007).
The role of autophagy in the death of L1210 leukemia cells initiated by the new antitumor agents, XK469 and SH80.
  Mol Cancer Ther, 6, 370-379.  
17961201 D.Vauzour, K.Vafeiadou, C.Rice-Evans, R.J.Williams, and J.P.Spencer (2007).
Activation of pro-survival Akt and ERK1/2 signalling pathways underlie the anti-apoptotic effects of flavanones in cortical neurons.
  J Neurochem, 103, 1355-1367.  
18181689 E.R.Sharlow, S.Leimgruber, T.Y.Shun, and J.S.Lazo (2007).
Development and implementation of a miniaturized high-throughput time-resolved fluorescence energy transfer assay to identify small molecule inhibitors of polo-like kinase 1.
  Assay Drug Dev Technol, 5, 723-735.  
17638533 F.Zanella, A.Rosado, F.Blanco, B.R.Henderson, A.Carnero, and W.Link (2007).
An HTS approach to screen for antagonists of the nuclear export machinery using high content cell-based assays.
  Assay Drug Dev Technol, 5, 333-341.  
17298385 H.Schroeter, P.Bahia, J.P.Spencer, O.Sheppard, M.Rattray, E.Cadenas, C.Rice-Evans, and R.J.Williams (2007).
(-)Epicatechin stimulates ERK-dependent cyclic AMP response element activity and up-regulates GluR2 in cortical neurons.
  J Neurochem, 101, 1596-1606.  
17379147 H.Yuan, K.R.Barnes, R.Weissleder, L.Cantley, and L.Josephson (2007).
Covalent reactions of wortmannin under physiological conditions.
  Chem Biol, 14, 321-328.  
17701137 J.Lättig, M.Böhl, P.Fischer, S.Tischer, C.Tietböhl, M.Menschikowski, H.O.Gutzeit, P.Metz, and M.T.Pisabarro (2007).
Mechanism of inhibition of human secretory phospholipase A2 by flavonoids: rationale for lead design.
  J Comput Aided Mol Des, 21, 473-483.  
18850181 J.P.Spencer (2007).
The interactions of flavonoids within neuronal signalling pathways.
  Genes Nutr, 2, 257-273.  
17698806 J.R.Gledhill, M.G.Montgomery, A.G.Leslie, and J.E.Walker (2007).
Mechanism of inhibition of bovine F1-ATPase by resveratrol and related polyphenols.
  Proc Natl Acad Sci U S A, 104, 13632-13637.
PDB codes: 2jiz 2jj1 2jj2
17462572 J.Yang, A.Shamji, S.Matchacheep, and S.L.Schreiber (2007).
Identification of a small-molecule inhibitor of class Ia PI3Ks with cell-based screening.
  Chem Biol, 14, 371-377.  
17562705 L.M.Ballou, E.S.Selinger, J.Y.Choi, D.G.Drueckhammer, and R.Z.Lin (2007).
Inhibition of mammalian target of rapamycin signaling by 2-(morpholin-1-yl)pyrimido[2,1-alpha]isoquinolin-4-one.
  J Biol Chem, 282, 24463-24470.  
17355970 M.Guha, S.Srinivasan, G.Biswas, and N.G.Avadhani (2007).
Activation of a novel calcineurin-mediated insulin-like growth factor-1 receptor pathway, altered metabolism, and tumor cell invasion in cells subjected to mitochondrial respiratory stress.
  J Biol Chem, 282, 14536-14546.  
17258189 M.K.Jungnickel, K.A.Sutton, Y.Wang, and H.M.Florman (2007).
Phosphoinositide-dependent pathways in mouse sperm are regulated by egg ZP3 and drive the acrosome reaction.
  Dev Biol, 304, 116-126.  
17184770 M.Vergés, I.Sebastián, and K.E.Mostov (2007).
Phosphoinositide 3-kinase regulates the role of retromer in transcytosis of the polymeric immunoglobulin receptor.
  Exp Cell Res, 313, 707-718.  
17355172 N.Kannan, S.S.Taylor, Y.Zhai, J.C.Venter, and G.Manning (2007).
Structural and functional diversity of the microbial kinome.
  PLoS Biol, 5, e17.  
18046441 R.C.Castellino, and D.L.Durden (2007).
Mechanisms of Disease: the PI3K-Akt-PTEN signaling node--an intercept point for the control of angiogenesis in brain tumors.
  Nat Clin Pract Neurol, 3, 682-693.  
17682062 T.Bosse, J.Ehinger, A.Czuchra, S.Benesch, A.Steffen, X.Wu, K.Schloen, H.H.Niemann, G.Scita, T.E.Stradal, C.Brakebusch, and K.Rottner (2007).
Cdc42 and phosphoinositide 3-kinase drive Rac-mediated actin polymerization downstream of c-Met in distinct and common pathways.
  Mol Cell Biol, 27, 6615-6628.  
17920279 T.Crabbe, M.J.Welham, and S.G.Ward (2007).
The PI3K inhibitor arsenal: choose your weapon!
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17603562 V.Wells, J.Downward, and L.Mallucci (2007).
Functional inhibition of PI3K by the betaGBP molecule suppresses Ras-MAPK signalling to block cell proliferation.
  Oncogene, 26, 7709-7714.  
17669540 Y.Bae, T.A.Diezi, A.Zhao, and G.S.Kwon (2007).
Mixed polymeric micelles for combination cancer chemotherapy through the concurrent delivery of multiple chemotherapeutic agents.
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17031854 Y.H.Kim, and Y.J.Lee (2007).
TRAIL apoptosis is enhanced by quercetin through Akt dephosphorylation.
  J Cell Biochem, 100, 998.  
17300515 Y.Hernandez, G.Zamora, S.Ray, J.Chapoy, E.Chavez, R.Valvarde, E.Williams, S.B.Aley, and S.Das (2007).
Transcriptional analysis of three major putative phosphatidylinositol kinase genes in a parasitic protozoan, Giardia lamblia.
  J Eukaryot Microbiol, 54, 29-32.  
16537514 A.Schirmer, J.Kennedy, S.Murli, R.Reid, and D.V.Santi (2006).
Targeted covalent inactivation of protein kinases by resorcylic acid lactone polyketides.
  Proc Natl Acad Sci U S A, 103, 4234-4239.  
16835237 B.S.Hall, C.Gabernet-Castello, A.Voak, D.Goulding, S.K.Natesan, and M.C.Field (2006).
TbVps34, the trypanosome orthologue of Vps34, is required for Golgi complex segregation.
  J Biol Chem, 281, 27600-27612.  
16824925 C.C.Hong, Q.P.Peterson, J.Y.Hong, and R.T.Peterson (2006).
Artery/vein specification is governed by opposing phosphatidylinositol-3 kinase and MAP kinase/ERK signaling.
  Curr Biol, 16, 1366-1372.  
17119643 C.Sánchez, C.Méndez, and J.A.Salas (2006).
Indolocarbazole natural products: occurrence, biosynthesis, and biological activity.
  Nat Prod Rep, 23, 1007-1045.  
16374778 G.Cohen, C.Makranz, M.Spira, T.Kodama, F.Reichert, and S.Rotshenker (2006).
Non-PKC DAG/phorbol-ester receptor(s) inhibit complement receptor-3 and nPKC inhibit scavenger receptor-AI/II-mediated myelin phagocytosis but cPKC, PI3k, and PLCgamma activate myelin phagocytosis by both.
  Glia, 53, 538-550.  
16773240 H.Schmidinger, A.Hermetter, and R.Birner-Gruenberger (2006).
Activity-based proteomics: enzymatic activity profiling in complex proteomes.
  Amino Acids, 30, 333-350.  
16581863 K.Matsushita, and D.G.Puro (2006).
Topographical heterogeneity of K(IR) currents in pericyte-containing microvessels of the rat retina: effect of diabetes.
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16557283 K.Strebhardt, and A.Ullrich (2006).
Targeting polo-like kinase 1 for cancer therapy.
  Nat Rev Cancer, 6, 321-330.  
16467781 M.Santra, M.Katakowski, R.L.Zhang, Z.G.Zhang, H.Meng, F.Jiang, and M.Chopp (2006).
Protection of adult mouse progenitor cells and human glioma cells by de novo decorin expression in an oxygen- and glucose-deprived cell culture model system.
  J Cereb Blood Flow Metab, 26, 1311-1322.  
16549781 N.M.Storey, S.Gentile, H.Ullah, A.Russo, M.Muessel, C.Erxleben, and D.L.Armstrong (2006).
Rapid signaling at the plasma membrane by a nuclear receptor for thyroid hormone.
  Proc Natl Acad Sci U S A, 103, 5197-5201.  
16359858 Q.W.Fan, and W.A.Weiss (2006).
Chemical genetic approaches to the development of cancer therapeutics.
  Curr Opin Genet Dev, 16, 85-91.  
16627617 Q.Yang, K.Inoki, E.Kim, and K.L.Guan (2006).
TSC1/TSC2 and Rheb have different effects on TORC1 and TORC2 activity.
  Proc Natl Acad Sci U S A, 103, 6811-6816.  
16288223 R.Abdul-Ghani, V.Serra, B.Györffy, K.Jürchott, A.Solf, M.Dietel, and R.Schäfer (2006).
The PI3K inhibitor LY294002 blocks drug export from resistant colon carcinoma cells overexpressing MRP1.
  Oncogene, 25, 1743-1752.  
16404616 R.R.Kuang, F.Qian, Z.Li, and D.Z.Wei (2006).
Study on improving the selectivity of compounds that inhibit two PI3Ks (gamma and delta).
  J Mol Model, 12, 445-452.  
16707026 S.S.Cox, M.van der Giezen, S.J.Tarr, M.R.Crompton, and J.Tovar (2006).
Evidence from bioinformatics, expression and inhibition studies of phosphoinositide-3 kinase signalling in Giardia intestinalis.
  BMC Microbiol, 6, 45.  
16622124 S.Yaguchi, Y.Fukui, I.Koshimizu, H.Yoshimi, T.Matsuno, H.Gouda, S.Hirono, K.Yamazaki, and T.Yamori (2006).
Antitumor activity of ZSTK474, a new phosphatidylinositol 3-kinase inhibitor.
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16310864 T.N.Wells, C.A.Power, J.P.Shaw, and A.E.Proudfoot (2006).
Chemokine blockers--therapeutics in the making?
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17080027 T.Rückle, M.K.Schwarz, and C.Rommel (2006).
PI3Kgamma inhibition: towards an 'aspirin of the 21st century'?
  Nat Rev Drug Discov, 5, 903-918.  
16647110 Z.A.Knight, B.Gonzalez, M.E.Feldman, E.R.Zunder, D.D.Goldenberg, O.Williams, R.Loewith, D.Stokoe, A.Balla, B.Toth, T.Balla, W.A.Weiss, R.L.Williams, and K.M.Shokat (2006).
A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling.
  Cell, 125, 733-747.
PDB codes: 2chw 2chx 2chz
16149114 C.Drahl, B.F.Cravatt, and E.J.Sorensen (2005).
Protein-reactive natural products.
  Angew Chem Int Ed Engl, 44, 5788-5809.  
15778971 D.G.Covell, A.Wallqvist, R.Huang, N.Thanki, A.A.Rabow, and X.J.Lu (2005).
Linking tumor cell cytotoxicity to mechanism of drug action: an integrated analysis of gene expression, small-molecule screening and structural databases.
  Proteins, 59, 403-433.  
15967799 E.A.Waxman, and D.R.Lynch (2005).
N-methyl-D-aspartate receptor subtype mediated bidirectional control of p38 mitogen-activated protein kinase.
  J Biol Chem, 280, 29322-29333.  
15940673 E.Aksoy, W.Vanden Berghe, S.Detienne, Z.Amraoui, K.A.Fitzgerald, G.Haegeman, M.Goldman, and F.Willems (2005).
Inhibition of phosphoinositide 3-kinase enhances TRIF-dependent NF-kappa B activation and IFN-beta synthesis downstream of Toll-like receptor 3 and 4.
  Eur J Immunol, 35, 2200-2209.  
15879597 F.Soulet, K.Bailly, S.Roga, A.C.Lavigne, F.Amalric, and G.Bouche (2005).
Exogenously added fibroblast growth factor 2 (FGF-2) to NIH3T3 cells interacts with nuclear ribosomal S6 kinase 2 (RSK2) in a cell cycle-dependent manner.
  J Biol Chem, 280, 25604-25610.  
15845472 J.Sissons, K.S.Kim, M.Stins, S.Jayasekera, S.Alsam, and N.A.Khan (2005).
Acanthamoeba castellanii induces host cell death via a phosphatidylinositol 3-kinase-dependent mechanism.
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16203968 J.Zhang, and H.F.Lodish (2005).
Identification of K-ras as the major regulator for cytokine-dependent Akt activation in erythroid progenitors in vivo.
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15975929 M.C.Yee, S.C.Fas, M.M.Stohlmeyer, T.J.Wandless, and K.A.Cimprich (2005).
A cell-permeable, activity-based probe for protein and lipid kinases.
  J Biol Chem, 280, 29053-29059.  
16127437 M.Camps, T.Rückle, H.Ji, V.Ardissone, F.Rintelen, J.Shaw, C.Ferrandi, C.Chabert, C.Gillieron, B.Françon, T.Martin, D.Gretener, D.Perrin, D.Leroy, P.A.Vitte, E.Hirsch, M.P.Wymann, R.Cirillo, M.K.Schwarz, and C.Rommel (2005).
Blockade of PI3Kgamma suppresses joint inflammation and damage in mouse models of rheumatoid arthritis.
  Nat Med, 11, 936-943.
PDB codes: 2a4z 2a5u
15739165 M.J.Thomas, A.Smith, D.H.Head, L.Milne, A.Nicholls, W.Pearce, B.Vanhaesebroeck, M.P.Wymann, E.Hirsch, A.Trifilieff, C.Walker, P.Finan, and J.Westwick (2005).
Airway inflammation: chemokine-induced neutrophilia and the class I phosphoinositide 3-kinases.
  Eur J Immunol, 35, 1283-1291.  
15917886 P.Wipf, and R.J.Halter (2005).
Chemistry and biology of wortmannin.
  Org Biomol Chem, 3, 2053-2061.  
15838873 W.Link, A.Rosado, J.Fominaya, J.E.Thomas, and A.Carnero (2005).
Membrane localization of all class I PI 3-kinase isoforms suppresses c-Myc-induced apoptosis in Rat1 fibroblasts via Akt.
  J Cell Biochem, 95, 979-989.  
15590660 X.Zhang, P.Shan, J.Alam, X.Y.Fu, and P.J.Lee (2005).
Carbon monoxide differentially modulates STAT1 and STAT3 and inhibits apoptosis via a phosphatidylinositol 3-kinase/Akt and p38 kinase-dependent STAT3 pathway during anoxia-reoxygenation injury.
  J Biol Chem, 280, 8714-8721.  
15009668 A.J.Crossthwaite, H.Valli, and R.J.Williams (2004).
Inhibiting Src family tyrosine kinase activity blocks glutamate signalling to ERK1/2 and Akt/PKB but not JNK in cultured striatal neurones.
  J Neurochem, 88, 1127-1139.  
15042695 C.A.Bradham, E.L.Miranda, and D.R.McClay (2004).
PI3K inhibitors block skeletogenesis but not patterning in sea urchin embryos.
  Dev Dyn, 229, 713-721.  
15314062 D.A.Solomon, M.C.Cardoso, and E.S.Knudsen (2004).
Dynamic targeting of the replication machinery to sites of DNA damage.
  J Cell Biol, 166, 455-463.  
14715649 D.J.Levinthal, and D.B.DeFranco (2004).
Transient phosphatidylinositol 3-kinase inhibition protects immature primary cortical neurons from oxidative toxicity via suppression of extracellular signal-regulated kinase activation.
  J Biol Chem, 279, 11206-11213.  
15149544 E.K.Schmidt, S.Fichelson, and S.M.Feller (2004).
PI3 kinase is important for Ras, MEK and Erk activation of Epo-stimulated human erythroid progenitors.
  BMC Biol, 2, 7.  
15489221 E.U.Kurz, P.Douglas, and S.P.Lees-Miller (2004).
Doxorubicin activates ATM-dependent phosphorylation of multiple downstream targets in part through the generation of reactive oxygen species.
  J Biol Chem, 279, 53272-53281.  
15492127 F.Fallarino, R.Bianchi, C.Orabona, C.Vacca, M.L.Belladonna, M.C.Fioretti, D.V.Serreze, U.Grohmann, and P.Puccetti (2004).
CTLA-4-Ig activates forkhead transcription factors and protects dendritic cells from oxidative stress in nonobese diabetic mice.
  J Exp Med, 200, 1051-1062.  
14748662 H.B.Newton (2004).
Molecular neuro-oncology and development of targeted therapeutic strategies for brain tumors. Part 2: PI3K/Akt/PTEN, mTOR, SHH/PTCH and angiogenesis.
  Expert Rev Anticancer Ther, 4, 105-128.  
15031492 M.E.Noble, J.A.Endicott, and L.N.Johnson (2004).
Protein kinase inhibitors: insights into drug design from structure.
  Science, 303, 1800-1805.  
15019969 R.J.Williams, J.P.Spencer, and C.Rice-Evans (2004).
Flavonoids: antioxidants or signalling molecules?
  Free Radic Biol Med, 36, 838-849.  
15086530 S.M.Dravid, D.G.Baden, and T.F.Murray (2004).
Brevetoxin activation of voltage-gated sodium channels regulates Ca dynamics and ERK1/2 phosphorylation in murine neocortical neurons.
  J Neurochem, 89, 739-749.  
15239392 T.Tauchi, and K.Ohyashiki (2004).
Imatinib mesylate in combination with other chemotherapeutic agents for chronic myelogenous leukemia.
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12697751 A.G.Camacho, A.Gual, R.Lurz, P.Tavares, and J.C.Alonso (2003).
Bacillus subtilis bacteriophage SPP1 DNA packaging motor requires terminase and portal proteins.
  J Biol Chem, 278, 23251-23259.  
12566459 I.Usui, T.Imamura, J.Huang, H.Satoh, and J.M.Olefsky (2003).
Cdc42 is a Rho GTPase family member that can mediate insulin signaling to glucose transport in 3T3-L1 adipocytes.
  J Biol Chem, 278, 13765-13774.  
12876289 K.Song, S.C.Cornelius, M.Reiss, and D.Danielpour (2003).
Insulin-like growth factor-I inhibits transcriptional responses of transforming growth factor-beta by phosphatidylinositol 3-kinase/Akt-dependent suppression of the activation of Smad3 but not Smad2.
  J Biol Chem, 278, 38342-38351.  
12871670 M.P.Wymann, M.Zvelebil, and M.Laffargue (2003).
Phosphoinositide 3-kinase signalling--which way to target?
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14646171 M.Shichijo, N.Yamamoto, H.Tsujishita, M.Kimata, H.Nagai, and T.Kokubo (2003).
Inhibition of syk activity and degranulation of human mast cells by flavonoids.
  Biol Pharm Bull, 26, 1685-1690.  
12502866 P.P.Naranatt, S.M.Akula, C.A.Zien, H.H.Krishnan, and B.Chandran (2003).
Kaposi's sarcoma-associated herpesvirus induces the phosphatidylinositol 3-kinase-PKC-zeta-MEK-ERK signaling pathway in target cells early during infection: implications for infectivity.
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12682053 R.L.Doughman, A.J.Firestone, M.L.Wojtasiak, M.W.Bunce, and R.A.Anderson (2003).
Membrane ruffling requires coordination between type Ialpha phosphatidylinositol phosphate kinase and Rac signaling.
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12652656 S.N.Wu, H.T.Chiang, A.Y.Shen, and Y.K.Lo (2003).
Differential effects of quercetin, a natural polyphenolic flavonoid, on L-type calcium current in pituitary tumor (GH3) cells and neuronal NG108-15 cells.
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12670534 S.Ward, Y.Sotsios, J.Dowden, I.Bruce, and P.Finan (2003).
Therapeutic potential of phosphoinositide 3-kinase inhibitors.
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12653748 T.T.Phan, P.See, E.Tran, T.T.Nguyen, S.Y.Chan, S.T.Lee, and H.Huynh (2003).
Suppression of insulin-like growth factor signalling pathway and collagen expression in keloid-derived fibroblasts by quercetin: its therapeutic potential use in the treatment and/or prevention of keloids.
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11687577 K.W.Thomas, M.M.Monick, J.M.Staber, T.Yarovinsky, A.B.Carter, and G.W.Hunninghake (2002).
Respiratory syncytial virus inhibits apoptosis and induces NF-kappa B activity through a phosphatidylinositol 3-kinase-dependent pathway.
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11790300 N.M.Storey, J.P.O'Bryan, and D.L.Armstrong (2002).
Rac and Rho mediate opposing hormonal regulation of the ether-a-go-go-related potassium channel.
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12151228 S.Djordjevic, and P.C.Driscoll (2002).
Structural insight into substrate specificity and regulatory mechanisms of phosphoinositide 3-kinases.
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11395417 B.Vanhaesebroeck, S.J.Leevers, K.Ahmadi, J.Timms, R.Katso, P.C.Driscoll, R.Woscholski, P.J.Parker, and M.D.Waterfield (2001).
Synthesis and function of 3-phosphorylated inositol lipids.
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11772237 C.P.Berrie (2001).
Phosphoinositide 3-kinase inhibition in cancer treatment.
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11689702 G.Guasch, V.Ollendorff, J.P.Borg, D.Birnbaum, and M.J.Pébusque (2001).
8p12 stem cell myeloproliferative disorder: the FOP-fibroblast growth factor receptor 1 fusion protein of the t(6;8) translocation induces cell survival mediated by mitogen-activated protein kinase and phosphatidylinositol 3-kinase/Akt/mTOR pathways.
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11812837 H.Xu, G.Ziegelin, W.Schröder, J.Frank, S.Ayora, J.C.Alonso, E.Lanka, and W.Saenger (2001).
Flavones inhibit the hexameric replicative helicase RepA.
  Nucleic Acids Res, 29, 5058-5066.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.