6gy0
From Proteopedia
mPI3Kd IN COMPLEX WITH AZ3
Structural highlights
FunctionPK3CD_MOUSE Phosphoinositide-3-kinase (PI3K) that phosphorylates PftdIns(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. Mediates immune responses. Plays a role in B-cell development, proliferation, migration, and function. Required for B-cell receptor (BCR) signaling. Mediates B-cell proliferation response to anti-IgM, anti-CD40 and IL4 stimulation. Promotes cytokine production in response to TLR4 and TLR9. Required for antibody class switch mediated by TLR9. Involved in the antigen presentation function of B-cells. Involved in B-cell chemotaxis in response to CXCL13 and sphingosine 1-phosphate (S1P). Required for proliferation, signaling and cytokine production of naive, effector and memory T-cells. Required for T-cell receptor (TCR) signaling. Mediates TCR signaling events at the immune synapse. Activation by TCR leads to antigen-dependent memory T-cell migration and retention to antigenic tissues. Together with PIK3CG participates in T-cell development. Contributes to T-helper cell expansion and differentiation. Required for T-cell migration mediated by homing receptors SELL/CD62L, CCR7 and S1PR1 and antigen dependent recruitment of T-cells. Together with PIK3CG is involved in natural killer (NK) cell development and migration towards the sites of inflammation. Participates in NK cell receptor activation. Have a role in NK cell maturation and cytokine production. Together with PIK3CG is involved in neutrophil chemotaxis and extravasation. Together with PIK3CG participates in neutrophil respiratory burst. Have important roles in mast-cell development and mast cell mediated allergic response. Involved in stem cell factor (SCF)-mediated proliferation, adhesion and migration. Required for allergen-IgE-induced degranulation and cytokine release. The lipid kinase activity is required for its biological function.[1] [2] [3] [4] [5] [6] [7] Publication Abstract from PubMedWe have discovered a class of PI3Kgamma inhibitors exhibiting over 1,000-fold selectivity over PI3Kalpha and PI3Kbeta. On the basis of X-ray crystallography, hydrogen-deuterium exchange-mass spectrometry and surface plasmon resonance experiments we propose that the cyclopropylethyl moiety displaces the DFG motif of the enzyme away from the adenosine tri-phosphate binding site, inducing a large conformational change in both the kinase- and helical domains of PI3Kgamma. Site directed mutagenesis explained how the conformational changes occur. Our results suggest that these cyclopropylethyl substituted compounds selectively inhibit the active state of PI3Kgamma, which is unique to these compounds and to the PI3Kgamma isoform, explaining their excellent potency and unmatched isoform selectivity that were confirmed in cellular systems. This is the first example of a Class I PI3K inhibitor achieving its selectivity by affecting the DFG motif in a manner that bears similarity to DFG in/out for type II protein kinase inhibitors. A class of highly selective inhibitors bind to an active state of PI3Kgamma.,Gangadhara G, Dahl G, Bohnacker T, Rae R, Gunnarsson J, Blaho S, Oster L, Lindmark H, Karabelas K, Pemberton N, Tyrchan C, Mogemark M, Wymann MP, Williams RL, Perry MWD, Papavoine T, Petersen J Nat Chem Biol. 2019 Feb 4. pii: 10.1038/s41589-018-0215-0. doi:, 10.1038/s41589-018-0215-0. PMID:30718815[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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