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3zh8

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Revision as of 20:27, 5 August 2016

A novel small molecule aPKC inhibitor

Structural highlights

3zh8 is a 3 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, , ,
NonStd Res:
Activity:	Protein kinase C, with EC number 2.7.11.13
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[KPCI_HUMAN] Calcium- and diacylglycerol-independent serine/ threonine-protein kinase that plays a general protective role against apoptotic stimuli, is involved in NF-kappa-B activation, cell survival, differentiation and polarity, and contributes to the regulation of microtubule dynamics in the early secretory pathway. Is necessary for BCR-ABL oncogene-mediated resistance to apoptotic drug in leukemia cells, protecting leukemia cells against drug-induced apoptosis. In cultured neurons, prevents amyloid beta protein-induced apoptosis by interrupting cell death process at a very early step. In glioblastoma cells, may function downstream of phosphatidylinositol 3-kinase (PI(3)K) and PDPK1 in the promotion of cell survival by phosphorylating and inhibiting the pro-apoptotic factor BAD. Can form a protein complex in non-small cell lung cancer (NSCLC) cells with PARD6A and ECT2 and regulate ECT2 oncogenic activity by phosphorylation, which in turn promotes transformed growth and invasion. In response to nerve growth factor (NGF), acts downstream of SRC to phosphorylate and activate IRAK1, allowing the subsequent activation of NF-kappa-B and neuronal cell survival. Functions in the organization of the apical domain in epithelial cells by phosphorylating EZR. This step is crucial for activation and normal distribution of EZR at the early stages of intestinal epithelial cell differentiation. Forms a protein complex with LLGL1 and PARD6B independently of PARD3 to regulate epithelial cell polarity. Plays a role in microtubule dynamics in the early secretory pathway through interaction with RAB2A and GAPDH and recruitment to vesicular tubular clusters (VTCs). In human coronary artery endothelial cells (HCAEC), is activated by saturated fatty acids and mediates lipid-induced apoptosis.^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8] ^[9] ^[10] ^[11] ^[12] ^[13] ^[14]

Publication Abstract from PubMed

The atypical protein kinase C (aPKC) isoforms iota (iota) and zeta (zeta) play crucial roles in the formation and maintenance of cell polarity and represent attractive anti-oncogenic drug targets in Ras-dependent tumours. To date, few isoform-specific chemical biology tools are available to inhibit aPKC catalytic activity. Here we describe the identification and functional characterization of potent and selective thieno[2,3-d]pyrimidine-based chemical inhibitors of aPKCs. A crystal structure of human PKCiota kinase domain bound to a representative compound, CRT0066854, reveals the basis for potent and selective chemical inhibition. Furthermore, CRT0066854 displaces a crucial Asn-Phe-Asp motif that is part of the adenosine-binding pocket and engages an acidic patch used by arginine-rich PKC substrates. We show that CRT0066854 inhibits the lethal giant larvae 2 (LLGL2) phosphorylation in cell lines and exhibits phenotypic effects in a range of cell-based assays. We conclude that this compound has utility as a chemical tool to modulate aPKC activity in vitro and in vivo and may guide the search for further aPKC-selective inhibitors.

Adenosine-binding motif mimicry and cellular effects of a thieno[2,3-d]pyrimidine-based chemical inhibitor of atypical protein kinase C isozymes.,Kjaer S, Linch M, Purkiss A, Kostelecky B, Knowles PP, Rosse C, Riou P, Soudy C, Kaye S, Patel B, Soriano E, Murray-Rust J, Barton C, Dillon C, Roffey J, Parker PJ, McDonald NQ Biochem J. 2013 Feb 18. PMID:23418854^[15]

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

References

↑ Selbie LA, Schmitz-Peiffer C, Sheng Y, Biden TJ. Molecular cloning and characterization of PKC iota, an atypical isoform of protein kinase C derived from insulin-secreting cells. J Biol Chem. 1993 Nov 15;268(32):24296-302. PMID:8226978
↑ Murray NR, Fields AP. Atypical protein kinase C iota protects human leukemia cells against drug-induced apoptosis. J Biol Chem. 1997 Oct 31;272(44):27521-4. PMID:9346882
↑ Wooten MW, Seibenhener ML, Zhou G, Vandenplas ML, Tan TH. Overexpression of atypical PKC in PC12 cells enhances NGF-responsiveness and survival through an NF-kappaB dependent pathway. Cell Death Differ. 1999 Aug;6(8):753-64. PMID:10467349 doi:10.1038/sj.cdd.4400548
↑ Sanz L, Sanchez P, Lallena MJ, Diaz-Meco MT, Moscat J. The interaction of p62 with RIP links the atypical PKCs to NF-kappaB activation. EMBO J. 1999 Jun 1;18(11):3044-53. PMID:10356400 doi:10.1093/emboj/18.11.3044
↑ Spitaler M, Villunger A, Grunicke H, Uberall F. Unique structural and functional properties of the ATP-binding domain of atypical protein kinase C-iota. J Biol Chem. 2000 Oct 27;275(43):33289-96. PMID:10906326 doi:10.1074/jbc.M002742200
↑ Xie J, Guo Q, Zhu H, Wooten MW, Mattson MP. Protein kinase C iota protects neural cells against apoptosis induced by amyloid beta-peptide. Brain Res Mol Brain Res. 2000 Oct 20;82(1-2):107-13. PMID:11042363
↑ Tisdale EJ. Glyceraldehyde-3-phosphate dehydrogenase is phosphorylated by protein kinase Ciota /lambda and plays a role in microtubule dynamics in the early secretory pathway. J Biol Chem. 2002 Feb 1;277(5):3334-41. Epub 2001 Nov 27. PMID:11724794 doi:10.1074/jbc.M109744200
↑ Tisdale EJ, Wang J, Silver RB, Artalejo CR. Atypical protein kinase C plays a critical role in protein transport from pre-Golgi intermediates. J Biol Chem. 2003 Sep 26;278(39):38015-21. Epub 2003 Jul 17. PMID:12871960 doi:10.1074/jbc.M305381200
↑ Mamidipudi V, Lin C, Seibenhener ML, Wooten MW. Regulation of interleukin receptor-associated kinase (IRAK) phosphorylation and signaling by iota protein kinase C. J Biol Chem. 2004 Feb 6;279(6):4161-5. Epub 2003 Dec 18. PMID:14684752 doi:10.1074/jbc.C300431200
↑ Regala RP, Weems C, Jamieson L, Copland JA, Thompson EA, Fields AP. Atypical protein kinase Ciota plays a critical role in human lung cancer cell growth and tumorigenicity. J Biol Chem. 2005 Sep 2;280(35):31109-15. Epub 2005 Jul 1. PMID:15994303 doi:M505402200
↑ Wald FA, Oriolo AS, Mashukova A, Fregien NL, Langshaw AH, Salas PJ. Atypical protein kinase C (iota) activates ezrin in the apical domain of intestinal epithelial cells. J Cell Sci. 2008 Mar 1;121(Pt 5):644-54. doi: 10.1242/jcs.016246. Epub 2008 Feb, 12. PMID:18270268 doi:10.1242/jcs.016246
↑ Staiger K, Schatz U, Staiger H, Weyrich P, Haas C, Guirguis A, Machicao F, Haring HU, Kellerer M. Protein kinase C iota mediates lipid-induced apoptosis of human coronary artery endothelial cells. Microvasc Res. 2009 Jun;78(1):40-4. doi: 10.1016/j.mvr.2009.01.014. Epub 2009 Mar, 25. PMID:19327373 doi:10.1016/j.mvr.2009.01.014
↑ Desai S, Pillai P, Win-Piazza H, Acevedo-Duncan M. PKC-iota promotes glioblastoma cell survival by phosphorylating and inhibiting BAD through a phosphatidylinositol 3-kinase pathway. Biochim Biophys Acta. 2011 Jun;1813(6):1190-7. doi: 10.1016/j.bbamcr.2011.03.007., Epub 2011 Mar 17. PMID:21419810 doi:10.1016/j.bbamcr.2011.03.007
↑ Justilien V, Jameison L, Der CJ, Rossman KL, Fields AP. Oncogenic activity of Ect2 is regulated through protein kinase C iota-mediated phosphorylation. J Biol Chem. 2011 Mar 11;286(10):8149-57. doi: 10.1074/jbc.M110.196113. Epub 2010, Dec 28. PMID:21189248 doi:10.1074/jbc.M110.196113
↑ Kjaer S, Linch M, Purkiss A, Kostelecky B, Knowles PP, Rosse C, Riou P, Soudy C, Kaye S, Patel B, Soriano E, Murray-Rust J, Barton C, Dillon C, Roffey J, Parker PJ, McDonald NQ. Adenosine-binding motif mimicry and cellular effects of a thieno[2,3-d]pyrimidine-based chemical inhibitor of atypical protein kinase C isozymes. Biochem J. 2013 Feb 18. PMID:23418854 doi:http://dx.doi.org/10.1042/BJ20121871

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/3zh8"

@@ Line 1: / Line 1: @@
 ==A novel small molecule aPKC inhibitor==
 <StructureSection load='3zh8' size='340' side='right' caption='[[3zh8]], [[Resolution|resolution]] 2.74&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[3zh8]] is a 3 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=3ZH8 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3ZH8 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[3zh8]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3ZH8 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3ZH8 FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=C58:(2S)-3-PHENYL-N~1~-[2-(PYRIDIN-4-YL)-5,6,7,8-TETRAHYDRO[1]BENZOTHIENO[2,3-D]PYRIMIDIN-4-YL]PROPANE-1,2-DIAMINE'>C58</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene></td></tr>
 <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene></td></tr>
 <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Protein_kinase_C Protein kinase C], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.13 2.7.11.13] </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=3zh8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3zh8 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3zh8 RCSB], [http://www.ebi.ac.uk/pdbsum/3zh8 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=3zh8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3zh8 OCA], [http://pdbe.org/3zh8 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3zh8 RCSB], [http://www.ebi.ac.uk/pdbsum/3zh8 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3zh8 ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 18: / Line 19: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 3zh8" style="background-color:#fffaf0;"></div>
 ==See Also==
@@ Line 25: / Line 27: @@
 __TOC__
 </StructureSection>
-[[Category: Homo sapiens]]
+[[Category: Human]]
 [[Category: Protein kinase C]]
 [[Category: Kjaer, S]]

3zh8

From Proteopedia

Revision as of 20:27, 5 August 2016

A novel small molecule aPKC inhibitor

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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