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The Structure of PI3K
Structure of PI3K
The Catalytic Subunit
The Catalytic Subunit (P110) of Class 1 PI3Ks
The catalytic subunit, P110 has several isoforms that associate with different classes of PI3Ks. P110α, β, and δ associate with Class IA PI3Ks while p110γ associates with Class 1B PI3ks.  The an N-terminal adaptor-binding domain (ABD), a Ras binding domain (RBD) a C2 domain that likely binds to the cellular membrane, a helical domain (HD) with unknown function, and the actual catalytic kinase domain.  The actions of these domains are coordinated by the nSH2 communicating domain in p85.
Communication between nSH2 & The Catalytic Subunit Domains
(residues 340-345) is anchored into Helix α11K of the (residues 1017-1024) nSH2 interacts with the through a network of charge-charge interactions involving two loops on nSH2 (Residues 374-377 & 350-354) and C2 residues 364-371, a strong 
The , whose function isn’t thoroughly understood, interacts with nSH2 via charge interactions. The HD residue, . These residues are known hotspot mutations which are associated with various types of cancer.  This loop in which contains the hotspots (residues 542-546) is located precisely where The salt bridge formed between like PDGFR, eliminating nSH2-mediated inhibition of p110α and activating the enzyme to phosphorylate PIP2 into PIP3. The hotspot mutation at Glu 542 accomplishes the same thing by eliminating the salt bridge and uninhibiting p110α. It is the which used to convert PIP2 into PIP3. 
Model for Catalysis
Although no with bound substate analog has been solved, a model for PIP2 phosphorylation has been developed and is generally supported.  In this model, the headgroup of PIP2 is between the . This puts the 5-phosphate of PIP2 near Lys 973 and the . The and Lys 973 can bind the 4-Phosphate of PIP2 and help provide the Class I PI3Ks with their specificity for PIP2. Once PIP2 and ATP are bound, it is believed , deprotonating it at the C-3 Hydroxyl position creating a nucleophile. This nucleophile subsequently attacks the gamma phosphate of ATP producing PIP3.  </StructureSection>
- See Phosphoinositide 3-Kinases for the main page or PI3K Activation, Inhibition, & Medical Implications for PI3Ks medical importance.
- See Cancer for additional information.
- See Diabetes for additional information.
- ↑ 1.0 1.1 Hoedemaeker FJ, Siegal G, Roe SM, Driscoll PC, Abrahams JP. Crystal structure of the C-terminal SH2 domain of the p85alpha regulatory subunit of phosphoinositide 3-kinase: an SH2 domain mimicking its own substrate. J Mol Biol. 1999 Oct 1;292(4):763-70. PMID:10525402 doi:10.1006/jmbi.1999.3111
- ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 Wymann MP, Pirola L. Structure and function of phosphoinositide 3-kinases. Biochim Biophys Acta. 1998 Dec 8;1436(1-2):127-50. PMID:9838078
- ↑ Otsu M, Hiles I, Gout I, Fry MJ, Ruiz-Larrea F, Panayotou G, Thompson A, Dhand R, Hsuan J, Totty N, et al.. Characterization of two 85 kd proteins that associate with receptor tyrosine kinases, middle-T/pp60c-src complexes, and PI3-kinase. Cell. 1991 Apr 5;65(1):91-104. PMID:1707345
- ↑ 4.0 4.1 Batra-Safferling R, Granzin J, Modder S, Hoffmann S, Willbold D. Structural studies of the phosphatidylinositol 3-kinase (PI3K) SH3 domain in complex with a peptide ligand: role of the anchor residue in ligand binding. Biol Chem. 2010 Jan;391(1):33-42. PMID:19919182 doi:10.1515/BC.2010.003
- ↑ Koch CA, Anderson D, Moran MF, Ellis C, Pawson T. SH2 and SH3 domains: elements that control interactions of cytoplasmic signaling proteins. Science. 1991 May 3;252(5006):668-74. PMID:1708916
- ↑ Dombrosky-Ferlan PM, Corey SJ. Yeast two-hybrid in vivo association of the Src kinase Lyn with the proto-oncogene product Cbl but not with the p85 subunit of PI 3-kinase. Oncogene. 1997 May 1;14(17):2019-24. PMID:9160881 doi:10.1038/sj.onc.1201031
- ↑ Weber T, Schaffhausen B, Liu Y, Gunther UL. NMR structure of the N-SH2 of the p85 subunit of phosphoinositide 3-kinase complexed to a doubly phosphorylated peptide reveals a second phosphotyrosine binding site. Biochemistry. 2000 Dec 26;39(51):15860-9. PMID:11123912
- ↑ Miled N, Yan Y, Hon WC, Perisic O, Zvelebil M, Inbar Y, Schneidman-Duhovny D, Wolfson HJ, Backer JM, Williams RL. Mechanism of two classes of cancer mutations in the phosphoinositide 3-kinase catalytic subunit. Science. 2007 Jul 13;317(5835):239-42. PMID:17626883 doi:317/5835/239
- ↑ Nolte RT, Eck MJ, Schlessinger J, Shoelson SE, Harrison SC. Crystal structure of the PI 3-kinase p85 amino-terminal SH2 domain and its phosphopeptide complexes. Nat Struct Biol. 1996 Apr;3(4):364-74. PMID:8599763
- ↑ 10.0 10.1 10.2 10.3 10.4 Mandelker D, Gabelli SB, Schmidt-Kittler O, Zhu J, Cheong I, Huang CH, Kinzler KW, Vogelstein B, Amzel LM. A frequent kinase domain mutation that changes the interaction between PI3Kalpha and the membrane. Proc Natl Acad Sci U S A. 2009 Oct 6;106(40):16996-7001. Epub 2009 Sep 23. PMID:19805105
- ↑ Dhand R, Hiles I, Panayotou G, Roche S, Fry MJ, Gout I, Totty NF, Truong O, Vicendo P, Yonezawa K, et al.. PI 3-kinase is a dual specificity enzyme: autoregulation by an intrinsic protein-serine kinase activity. EMBO J. 1994 Feb 1;13(3):522-33. PMID:8313897
- ↑ von Willebrand M, Williams S, Saxena M, Gilman J, Tailor P, Jascur T, Amarante-Mendes GP, Green DR, Mustelin T. Modification of phosphatidylinositol 3-kinase SH2 domain binding properties by Abl- or Lck-mediated tyrosine phosphorylation at Tyr-688. J Biol Chem. 1998 Feb 13;273(7):3994-4000. PMID:9461588
- ↑ 13.0 13.1 Walker EH, Perisic O, Ried C, Stephens L, Williams RL. Structural insights into phosphoinositide 3-kinase catalysis and signalling. Nature. 1999 Nov 18;402(6759):313-20. PMID:10580505 doi:10.1038/46319