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4xe0

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Revision as of 00:07, 26 January 2017

Idelalisib bound to the p110 subunit of PI3K delta

Structural highlights

4xe0 is a 1 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Activity:	Phosphatidylinositol-4,5-bisphosphate 3-kinase, with EC number 2.7.1.153
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[PK3CD_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 PubMed

Idelalisib (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

↑ Okkenhaug K, Bilancio A, Farjot G, Priddle H, Sancho S, Peskett E, Pearce W, Meek SE, Salpekar A, Waterfield MD, Smith AJ, Vanhaesebroeck B. Impaired B and T cell antigen receptor signaling in p110delta PI 3-kinase mutant mice. Science. 2002 Aug 9;297(5583):1031-4. Epub 2002 Jul 18. PMID:12130661 doi:http://dx.doi.org/10.1126/science.1073560
↑ Clayton E, Bardi G, Bell SE, Chantry D, Downes CP, Gray A, Humphries LA, Rawlings D, Reynolds H, Vigorito E, Turner M. A crucial role for the p110delta subunit of phosphatidylinositol 3-kinase in B cell development and activation. J Exp Med. 2002 Sep 16;196(6):753-63. PMID:12235209
↑ Ali K, Bilancio A, Thomas M, Pearce W, Gilfillan AM, Tkaczyk C, Kuehn N, Gray A, Giddings J, Peskett E, Fox R, Bruce I, Walker C, Sawyer C, Okkenhaug K, Finan P, Vanhaesebroeck B. Essential role for the p110delta phosphoinositide 3-kinase in the allergic response. Nature. 2004 Oct 21;431(7011):1007-11. PMID:15496927 doi:http://dx.doi.org/10.1038/nature02991
↑ Webb LM, Vigorito E, Wymann MP, Hirsch E, Turner M. Cutting edge: T cell development requires the combined activities of the p110gamma and p110delta catalytic isoforms of phosphatidylinositol 3-kinase. J Immunol. 2005 Sep 1;175(5):2783-7. PMID:16116162
↑ Jarmin SJ, David R, Ma L, Chai JG, Dewchand H, Takesono A, Ridley AJ, Okkenhaug K, Marelli-Berg FM. T cell receptor-induced phosphoinositide-3-kinase p110delta activity is required for T cell localization to antigenic tissue in mice. J Clin Invest. 2008 Mar;118(3):1154-64. doi: 10.1172/JCI33267. PMID:18259608 doi:http://dx.doi.org/10.1172/JCI33267
↑ Guo H, Samarakoon A, Vanhaesebroeck B, Malarkannan S. The p110 delta of PI3K plays a critical role in NK cell terminal maturation and cytokine/chemokine generation. J Exp Med. 2008 Sep 29;205(10):2419-35. doi: 10.1084/jem.20072327. Epub 2008 Sep , 22. PMID:18809712 doi:http://dx.doi.org/10.1084/jem.20072327
↑ Saudemont A, Garcon F, Yadi H, Roche-Molina M, Kim N, Segonds-Pichon A, Martin-Fontecha A, Okkenhaug K, Colucci F. p110gamma and p110delta isoforms of phosphoinositide 3-kinase differentially regulate natural killer cell migration in health and disease. Proc Natl Acad Sci U S A. 2009 Apr 7;106(14):5795-800. doi:, 10.1073/pnas.0808594106. Epub 2009 Mar 18. PMID:19297623 doi:http://dx.doi.org/10.1073/pnas.0808594106
↑ 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. Structural, Biochemical and Biophysical Characterization of Idelalisib Binding to Phosphoinositide 3-kinase Delta. J Biol Chem. 2015 Jan 28. pii: jbc.M114.634683. PMID:25631052 doi:http://dx.doi.org/10.1074/jbc.M114.634683

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4xe0"

@@ Line 1: / Line 1: @@
 ==Idelalisib bound to the p110 subunit of PI3K delta==
 <StructureSection load='4xe0' size='340' side='right' caption='[[4xe0]], [[Resolution|resolution]] 2.43&Aring;' scene=''>
@@ Line 5: / Line 6: @@
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=40L:5-FLUORO-3-PHENYL-2-[(1S)-1-(7H-PURIN-6-YLAMINO)PROPYL]QUINAZOLIN-4(3H)-ONE'>40L</scene></td></tr>
 <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Phosphatidylinositol-4,5-bisphosphate_3-kinase Phosphatidylinositol-4,5-bisphosphate 3-kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.153 2.7.1.153] </span></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4xe0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4xe0 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4xe0 RCSB], [http://www.ebi.ac.uk/pdbsum/4xe0 PDBsum]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4xe0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4xe0 OCA], [http://pdbe.org/4xe0 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4xe0 RCSB], [http://www.ebi.ac.uk/pdbsum/4xe0 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4xe0 ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 17: / Line 18: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 4xe0" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>

4xe0

From Proteopedia

Revision as of 00:07, 26 January 2017

Idelalisib bound to the p110 subunit of PI3K delta

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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