2j2i
From Proteopedia
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| - | [[Image:2j2i.jpg|left|200px]]<br /><applet load="2j2i" size="350" color="white" frame="true" align="right" spinBox="true" | ||
| - | caption="2j2i, resolution 1.90Å" /> | ||
| - | '''CRYSTAL STRUCTURE OF THE HUMAB PIM1 IN COMPLEX WITH LY333531'''<br /> | ||
| - | == | + | ==Crystal Structure of the humab PIM1 in complex with LY333531== |
| - | + | <StructureSection load='2j2i' size='340' side='right'caption='[[2j2i]], [[Resolution|resolution]] 1.90Å' scene=''> | |
| - | + | == Structural highlights == | |
| - | + | <table><tr><td colspan='2'>[[2j2i]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2J2I OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2J2I FirstGlance]. <br> | |
| - | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.9Å</td></tr> | |
| - | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=LY4:(9R)-9-[(DIMETHYLAMINO)METHYL]-6,7,10,11-TETRAHYDRO-9H,18H-5,21 12,17-DIMETHENODIBENZO[E,K]PYRROLO[3,4-H][1,4,13]OXADIAZACYCLOHEXADECINE-18,20-DIONE'>LY4</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | |
| - | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2j2i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2j2i OCA], [https://pdbe.org/2j2i PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2j2i RCSB], [https://www.ebi.ac.uk/pdbsum/2j2i PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2j2i ProSAT]</span></td></tr> | |
| - | + | </table> | |
| - | + | == Function == | |
| - | + | [https://www.uniprot.org/uniprot/PIM1_HUMAN PIM1_HUMAN] Proto-oncogene with serine/threonine kinase activity involved in cell survival and cell proliferation and thus providing a selective advantage in tumorigenesis. Exerts its oncogenic activity through: the regulation of MYC transcriptional activity, the regulation of cell cycle progression and by phosphorylation and inhibition of proapoptotic proteins (BAD, MAP3K5, FOXO3). Phosphorylation of MYC leads to an increase of MYC protein stability and thereby an increase of transcriptional activity. The stabilization of MYC exerted by PIM1 might explain partly the strong synergism between these two oncogenes in tumorigenesis. Mediates survival signaling through phosphorylation of BAD, which induces release of the anti-apoptotic protein Bcl-X(L)/BCL2L1. Phosphorylation of MAP3K5, an other proapoptotic protein, by PIM1, significantly decreases MAP3K5 kinase activity and inhibits MAP3K5-mediated phosphorylation of JNK and JNK/p38MAPK subsequently reducing caspase-3 activation and cell apoptosis. Stimulates cell cycle progression at the G1-S and G2-M transitions by phosphorylation of CDC25A and CDC25C. Phosphorylation of CDKN1A, a regulator of cell cycle progression at G1, results in the relocation of CDKN1A to the cytoplasm and enhanced CDKN1A protein stability. Promote cell cycle progression and tumorigenesis by down-regulating expression of a regulator of cell cycle progression, CDKN1B, at both transcriptional and post-translational levels. Phosphorylation of CDKN1B,induces 14-3-3-proteins binding, nuclear export and proteasome-dependent degradation. May affect the structure or silencing of chromatin by phosphorylating HP1 gamma/CBX3. Acts also as a regulator of homing and migration of bone marrow cells involving functional interaction with the CXCL12-CXCR4 signaling axis.<ref>PMID:1825810</ref> <ref>PMID:10664448</ref> <ref>PMID:12431783</ref> <ref>PMID:15528381</ref> <ref>PMID:16356754</ref> <ref>PMID:18593906</ref> <ref>PMID:19749799</ref> | |
| - | + | == Evolutionary Conservation == | |
| - | + | [[Image:Consurf_key_small.gif|200px|right]] | |
| - | + | Check<jmol> | |
| - | + | <jmolCheckbox> | |
| - | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/j2/2j2i_consurf.spt"</scriptWhenChecked> | |
| - | + | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | |
| - | + | <text>to colour the structure by Evolutionary Conservation</text> | |
| - | + | </jmolCheckbox> | |
| - | + | </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2j2i ConSurf]. | |
| - | + | <div style="clear:both"></div> | |
| - | + | <div style="background-color:#fffaf0;"> | |
| - | [[ | + | == Publication Abstract from PubMed == |
| - | + | Protein kinases play a pivotal role in cell signaling, and dysregulation of many kinases has been linked to disease development. A large number of kinase inhibitors are therefore currently under investigation in clinical trials, and so far seven inhibitors have been approved as anti-cancer drugs. In addition, kinase inhibitors are widely used as specific probes to study cell signaling, but systematic studies describing selectivity of these reagents across a panel of diverse kinases are largely lacking. Here we evaluated the specificity of 156 validated kinase inhibitors, including inhibitors used in clinical trials, against 60 human Ser/Thr kinases using a thermal stability shift assay. Our analysis revealed many unexpected cross-reactivities for inhibitors thought to be specific for certain targets. We also found that certain combinations of active-site residues in the ATP-binding site correlated with the detected ligand promiscuity and that some kinases are highly sensitive to inhibition using diverse chemotypes, suggesting them as preferred intervention points. Our results uncovered also inhibitor cross-reactivities that may lead to alternate clinical applications. For example, LY333'531, a PKCbeta inhibitor currently in phase III clinical trials, efficiently inhibited PIM1 kinase in our screen, a suggested target for treatment of leukemia. We determined the binding mode of this inhibitor by x-ray crystallography and in addition showed that LY333'531 induced cell death and significantly suppressed growth of leukemic cells from acute myeloid leukemia patients. | |
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| - | + | A systematic interaction map of validated kinase inhibitors with Ser/Thr kinases.,Fedorov O, Marsden B, Pogacic V, Rellos P, Muller S, Bullock AN, Schwaller J, Sundstrom M, Knapp S Proc Natl Acad Sci U S A. 2007 Dec 18;104(51):20523-8. Epub 2007 Dec 11. PMID:18077363<ref>PMID:18077363</ref> | |
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 2j2i" style="background-color:#fffaf0;"></div> | ||
| + | |||
| + | ==See Also== | ||
| + | *[[Serine/threonine protein kinase 3D structures|Serine/threonine protein kinase 3D structures]] | ||
| + | *[[3D structures of pim-1|3D structures of pim-1]] | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Arrowsmith C]] | ||
| + | [[Category: Bullock AN]] | ||
| + | [[Category: Debreczeni JE]] | ||
| + | [[Category: Edwards A]] | ||
| + | [[Category: Knapp S]] | ||
| + | [[Category: Sundstrom M]] | ||
| + | [[Category: Weigelt J]] | ||
| + | [[Category: Von Delft F]] | ||
Current revision
Crystal Structure of the humab PIM1 in complex with LY333531
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