6ilz
From Proteopedia
(Difference between revisions)
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| - | '''Unreleased structure''' | ||
| - | + | ==Crystal structure of PKCiota in complex with inhibitor== | |
| + | <StructureSection load='6ilz' size='340' side='right'caption='[[6ilz]], [[Resolution|resolution]] 3.26Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[6ilz]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6ILZ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6ILZ FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=AFU:2-amino-5-[3-(piperazin-1-yl)phenyl]-N-(pyridin-4-yl)pyridine-3-carboxamide'>AFU</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=6ilz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ilz OCA], [http://pdbe.org/6ilz PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ilz RCSB], [http://www.ebi.ac.uk/pdbsum/6ilz PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ilz ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [[http://www.uniprot.org/uniprot/KPCI_HUMAN 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.<ref>PMID:8226978</ref> <ref>PMID:9346882</ref> <ref>PMID:10467349</ref> <ref>PMID:10356400</ref> <ref>PMID:10906326</ref> <ref>PMID:11042363</ref> <ref>PMID:11724794</ref> <ref>PMID:12871960</ref> <ref>PMID:14684752</ref> <ref>PMID:15994303</ref> <ref>PMID:18270268</ref> <ref>PMID:19327373</ref> <ref>PMID:21419810</ref> <ref>PMID:21189248</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | The atypical protein kinase C-iota (PKC-iota) enzyme is implicated in various cancers and has been put forward as an attractive target for developing anticancer therapy. A high concentration biochemical screen identified pyridine fragment weakly inhibiting PKC-iota with IC50 = 424 muM. Driven by structure-activity relationships and guided by docking hypothesis, the weakly bound fragment was eventually optimized into a potent inhibitor of PKC-iota (IC50= 270 nM). Through the course of the optimization, an intermediate compound was crystallized with the protein, and careful analysis of the X-ray crystal structure revealed a unique binding mode involving the post-kinase domain (C-terminal tail) of PKC-iota. | ||
| - | + | Fragment-based Discovery of a Small-Molecule Protein Kinase C-iota Inhibitor Binding Post-kinase Domain Residues.,Kwiatkowski J, Baburajendran N, Poulsen A, Liu B, Tee DHY, Wong YX, Poh ZY, Ong EH, Dinie N, Cherian J, Jansson AE, Hill J, Keller TH, Hung AW ACS Med Chem Lett. 2019 Feb 15;10(3):318-323. doi:, 10.1021/acsmedchemlett.8b00546. eCollection 2019 Mar 14. PMID:30891133<ref>PMID:30891133</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| + | <div class="pdbe-citations 6ilz" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Protein kinase C]] | ||
| + | [[Category: Baburajendran, N]] | ||
| + | [[Category: Hill, J]] | ||
| + | [[Category: Atypical kinase]] | ||
| + | [[Category: Inhibitor]] | ||
| + | [[Category: Iota type]] | ||
| + | [[Category: Kinase]] | ||
| + | [[Category: Kinase domain]] | ||
| + | [[Category: Phosphorylation]] | ||
| + | [[Category: Pkciota]] | ||
| + | [[Category: Transferase]] | ||
Revision as of 06:51, 26 June 2019
Crystal structure of PKCiota in complex with inhibitor
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