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6ez6

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Revision as of 08:29, 17 January 2018

PI3 kinase delta in complex with Methyl 5-(4-(5-((4-isopropylpiperazin-1-yl)methyl)oxazol-2-yl)-1H-indazol-6-yl)-2-methoxynicotinate

Structural highlights

6ez6 is a 1 chain structure with sequence from Lk3 transgenic mice. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Related:	6eyz
Gene:	Pik3cd (LK3 transgenic mice)
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

Selective covalent inhibition of kinases by targeting poorly conserved cysteines has proven highly fruitful to date in the development of chemical probes and approved drugs. However, this approach is limited to ~200 kinases possessing such a cysteine near the ATP-binding pocket. Herein, we report a novel approach to achieve selective, irreversible kinase inhibition, by targeting the conserved catalytic lysine residue. We have illustrated our approach by developing selective, covalent PI3Kdelta inhibitors that exhibit nanomolar potency in cellular assays, and a duration of action >48 h in CD4+ T cells. Despite conservation of the lysine residue throughout the kinome, the lead compound shows high levels of selectivity over a selection of lipid and protein kinases in biochemical assays, as well as covalent binding to very few off-target proteins in live-cell proteomic studies. We anticipate this approach could offer an alternative general strategy, to targeting non-conserved cysteines, for the development of selective covalent kinase inhibitors.

Selectively targeting the kinome-conserved lysine of PI3Kdelta as a general approach to covalent kinase inhibition.,Dalton SE, Dittus L, Thomas DA, Convery MA, Nunes J, Bush JT, Evans JP, Werner T, Bantscheff M, Murphy JA, Campos S J Am Chem Soc. 2017 Dec 12. doi: 10.1021/jacs.7b08979. PMID:29232121^[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
↑ Dalton SE, Dittus L, Thomas DA, Convery MA, Nunes J, Bush JT, Evans JP, Werner T, Bantscheff M, Murphy JA, Campos S. Selectively targeting the kinome-conserved lysine of PI3Kdelta as a general approach to covalent kinase inhibition. J Am Chem Soc. 2017 Dec 12. doi: 10.1021/jacs.7b08979. PMID:29232121 doi:http://dx.doi.org/10.1021/jacs.7b08979

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/6ez6"

@@ Line 3: / Line 3: @@
 <StructureSection load='6ez6' size='340' side='right' caption='[[6ez6]], [[Resolution|resolution]] 2.04&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6ez6]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6EZ6 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6EZ6 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6ez6]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6EZ6 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6EZ6 FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=C5Z:methyl+2-methoxy-5-[4-[5-[(4-propan-2-ylpiperazin-1-yl)methyl]-1,3-oxazol-2-yl]-2~{H}-indazol-6-yl]pyridine-3-carboxylate'>C5Z</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[6eyz|6eyz]]</td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Pik3cd ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 LK3 transgenic mice])</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=6ez6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ez6 OCA], [http://pdbe.org/6ez6 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ez6 RCSB], [http://www.ebi.ac.uk/pdbsum/6ez6 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ez6 ProSAT]</span></td></tr>
@@ Line 24: / Line 25: @@
 __TOC__
 </StructureSection>
+[[Category: Lk3 transgenic mice]]
 [[Category: Phosphatidylinositol-4,5-bisphosphate 3-kinase]]
 [[Category: Campos, S]]

6ez6

From Proteopedia

Revision as of 08:29, 17 January 2018

PI3 kinase delta in complex with Methyl 5-(4-(5-((4-isopropylpiperazin-1-yl)methyl)oxazol-2-yl)-1H-indazol-6-yl)-2-methoxynicotinate

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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