4xe0 | pdb_00004xe0
Idelalisib bound to the p110 subunit of PI3K delta
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 PubMedIdelalisib (also known as GS-1101, CAL-101, IC489666 and Zydelig) is a phosphoinositide 3-kinase delta (PI3Kdelta) inhibitor that has recently been approved for the treatment of several hematological malignancies. Given its use in human diseases, we needed a clear picture of how idelalisib binds to and inhibits PI3Kdelta. Our data showed that idelalisib is a potent and selective inhibitor of the kinase activity of PI3Kdelta. A kinetic characterization clearly demonstrated ATP-competitive inhibition, and several additional biochemical and biophysical assays showed that the compound binds reversibly and non-covalently to the kinase. A crystal structure of idelalisib bound to the p110delta subunit of PI3Kdelta furthers our understanding of the binding interactions that confer the potency and selectivity of idelalisib. Structural, Biochemical and Biophysical Characterization of Idelalisib Binding to Phosphoinositide 3-kinase Delta.,Somoza JR, Koditek D, Villasenor AG, Novikov N, Wong MH, Liclican A, Xing W, Lagpacan L, Wang R, Schultz BE, Papalia GA, Samuel D, Lad L, McGrath ME J Biol Chem. 2015 Jan 28. pii: jbc.M114.634683. PMID:25631052[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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