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{{STRUCTURE_4ezk|  PDB=4ezk  |  SCENE=  }}
==Potent and Selective Inhibitors of PI3K-delta: Obtaining Isoform Selectivity from the Affinity Pocket and Tryptophan Shelf==
===Potent and Selective Inhibitors of PI3K-delta: Obtaining Isoform Selectivity from the Affinity Pocket and Tryptophan Shelf===
<StructureSection load='4ezk' size='340' side='right' caption='[[4ezk]], [[Resolution|resolution]] 2.80&Aring;' scene=''>
{{ABSTRACT_PUBMED_22672799}}
== Structural highlights ==
<table><tr><td colspan='2'>[[4ezk]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4EZK OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4EZK FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0SD:2-(1-{[2-(2H-INDAZOL-4-YL)-4-(MORPHOLIN-4-YL)PYRIDO[3,2-D]PYRIMIDIN-6-YL]METHYL}PIPERIDIN-4-YL)PROPAN-2-OL'>0SD</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4ezj|4ezj]], [[4ezl|4ezl]]</td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PIK3CG ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</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=4ezk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ezk OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4ezk RCSB], [http://www.ebi.ac.uk/pdbsum/4ezk PDBsum]</span></td></tr>
</table>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
A potent inhibitor of PI3Kdelta that is &gt;/= 200 fold selective for the remaining three Class I PI3K isoforms and additional kinases is described. The hypothesis for selectivity is illustrated through structure activity relationships and crystal structures of compounds bound to a K802T mutant of PI3Kgamma. Pharmacokinetic data in rats and mice support the use of 3 as a useful tool compound to use for in vivo studies.


==Function==
Potent and selective inhibitors of PI3Kdelta: obtaining isoform selectivity from the affinity pocket and tryptophan shelf.,Sutherlin DP, Baker S, Bisconte A, Blaney PM, Brown A, Chan BK, Chantry D, Castanedo G, DePledge P, Goldsmith P, Goldstein DM, Hancox T, Kaur J, Knowles D, Kondru R, Lesnick J, Lucas MC, Lewis C, Murray J, Nadin AJ, Nonomiya J, Pang J, Pegg N, Price S, Reif K, Safina BS, Salphati L, Staben S, Seward EM, Shuttleworth S, Sohal S, Sweeney ZK, Ultsch M, Waszkowycz B, Wei B Bioorg Med Chem Lett. 2012 Jul 1;22(13):4296-302. doi:, 10.1016/j.bmcl.2012.05.027. Epub 2012 May 17. PMID:22672799<ref>PMID:22672799</ref>
[[http://www.uniprot.org/uniprot/PK3CG_HUMAN PK3CG_HUMAN]] Phosphoinositide-3-kinase (PI3K) that phosphorylates PtdIns(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. Links G-protein coupled receptor activation to PIP3 production. Involved in immune, inflammatory and allergic responses. Modulates leukocyte chemotaxis to inflammatory sites and in response to chemoattractant agents. May control leukocyte polarization and migration by regulating the spatial accumulation of PIP3 and by regulating the organization of F-actin formation and integrin-based adhesion at the leading edge. Controls motility of dendritic cells. Together with PIK3CD is involved in natural killer (NK) cell development and migration towards the sites of inflammation. Participates in T-lymphocyte migration. Regulates T-lymphocyte proliferation and cytokine production. Together with PIK3CD participates in T-lymphocyte development. Required for B-lymphocyte development and signaling. Together with PIK3CD participates in neutrophil respiratory burst. Together with PIK3CD is involved in neutrophil chemotaxis and extravasation. Together with PIK3CB promotes platelet aggregation and thrombosis. Regulates alpha-IIb/beta-3 integrins (ITGA2B/ ITGB3) adhesive function in platelets downstream of P2Y12 through a lipid kinase activity-independent mechanism. May have also a lipid kinase activity-dependent function in platelet aggregation. Involved in endothelial progenitor cell migration. Negative regulator of cardiac contractility. Modulates cardiac contractility by anchoring protein kinase A (PKA) and PDE3B activation, reducing cAMP levels. Regulates cardiac contractility also by promoting beta-adrenergic receptor internalization by binding to ADRBK1 and by non-muscle tropomyosin phosphorylation. Also has serine/threonine protein kinase activity: both lipid and protein kinase activities are required for beta-adrenergic receptor endocytosis. May also have a scaffolding role in modulating cardiac contractility. Contributes to cardiac hypertrophy under pathological stress. Through simultaneous binding of PDE3B to RAPGEF3 and PIK3R6 is assembled in a signaling complex in which the PI3K gamma complex is activated by RAPGEF3 and which is involved in angiogenesis.<ref>PMID:7624799</ref> <ref>PMID:12163475</ref> <ref>PMID:15294162</ref> <ref>PMID:16094730</ref> <ref>PMID:21393242</ref>


==About this Structure==
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
[[4ezk]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4EZK OCA].
</div>


==Reference==
==See Also==
<references group="xtra"/><references/>
*[[Phosphoinositide 3-Kinases|Phosphoinositide 3-Kinases]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Murray, J M.]]
[[Category: Murray, J M]]
[[Category: Cytoplasmic]]
[[Category: Cytoplasmic]]
[[Category: Kinase p110]]
[[Category: Kinase p110]]

Revision as of 14:41, 21 December 2014

Potent and Selective Inhibitors of PI3K-delta: Obtaining Isoform Selectivity from the Affinity Pocket and Tryptophan ShelfPotent and Selective Inhibitors of PI3K-delta: Obtaining Isoform Selectivity from the Affinity Pocket and Tryptophan Shelf

Structural highlights

4ezk is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Gene:PIK3CG (Homo sapiens)
Resources:FirstGlance, OCA, RCSB, PDBsum

Publication Abstract from PubMed

A potent inhibitor of PI3Kdelta that is >/= 200 fold selective for the remaining three Class I PI3K isoforms and additional kinases is described. The hypothesis for selectivity is illustrated through structure activity relationships and crystal structures of compounds bound to a K802T mutant of PI3Kgamma. Pharmacokinetic data in rats and mice support the use of 3 as a useful tool compound to use for in vivo studies.

Potent and selective inhibitors of PI3Kdelta: obtaining isoform selectivity from the affinity pocket and tryptophan shelf.,Sutherlin DP, Baker S, Bisconte A, Blaney PM, Brown A, Chan BK, Chantry D, Castanedo G, DePledge P, Goldsmith P, Goldstein DM, Hancox T, Kaur J, Knowles D, Kondru R, Lesnick J, Lucas MC, Lewis C, Murray J, Nadin AJ, Nonomiya J, Pang J, Pegg N, Price S, Reif K, Safina BS, Salphati L, Staben S, Seward EM, Shuttleworth S, Sohal S, Sweeney ZK, Ultsch M, Waszkowycz B, Wei B Bioorg Med Chem Lett. 2012 Jul 1;22(13):4296-302. doi:, 10.1016/j.bmcl.2012.05.027. Epub 2012 May 17. PMID:22672799[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. ↑ Sutherlin DP, Baker S, Bisconte A, Blaney PM, Brown A, Chan BK, Chantry D, Castanedo G, DePledge P, Goldsmith P, Goldstein DM, Hancox T, Kaur J, Knowles D, Kondru R, Lesnick J, Lucas MC, Lewis C, Murray J, Nadin AJ, Nonomiya J, Pang J, Pegg N, Price S, Reif K, Safina BS, Salphati L, Staben S, Seward EM, Shuttleworth S, Sohal S, Sweeney ZK, Ultsch M, Waszkowycz B, Wei B. Potent and selective inhibitors of PI3Kdelta: obtaining isoform selectivity from the affinity pocket and tryptophan shelf. Bioorg Med Chem Lett. 2012 Jul 1;22(13):4296-302. doi:, 10.1016/j.bmcl.2012.05.027. Epub 2012 May 17. PMID:22672799 doi:http://dx.doi.org/10.1016/j.bmcl.2012.05.027

4ezk, resolution 2.80Å

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