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| | <StructureSection load='2iwi' size='340' side='right'caption='[[2iwi]], [[Resolution|resolution]] 2.80Å' scene=''> | | <StructureSection load='2iwi' size='340' side='right'caption='[[2iwi]], [[Resolution|resolution]] 2.80Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[2iwi]] is a 2 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=2IWI OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2IWI FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[2iwi]] is a 2 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=2IWI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2IWI FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=HB1:RUTHENIUM-PYRIDOCARBAZOLE-1'>HB1</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.8Å</td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </span></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=HB1:RUTHENIUM-PYRIDOCARBAZOLE-1'>HB1</scene></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=2iwi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2iwi OCA], [http://pdbe.org/2iwi PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2iwi RCSB], [http://www.ebi.ac.uk/pdbsum/2iwi PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2iwi ProSAT]</span></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=2iwi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2iwi OCA], [https://pdbe.org/2iwi PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2iwi RCSB], [https://www.ebi.ac.uk/pdbsum/2iwi PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2iwi ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/PIM2_HUMAN PIM2_HUMAN] Proto-oncogene with serine/threonine kinase activity involved in cell survival and cell proliferation. Exerts its oncogenic activity through: the regulation of MYC transcriptional activity, the regulation of cell cycle progression, the regulation of cap-dependent protein translation and through survival signaling by phosphorylation of a pro-apoptotic protein, BAD. Phosphorylation of MYC leads to an increase of MYC protein stability and thereby an increase transcriptional activity. The stabilization of MYC exerted by PIM2 might explain partly the strong synergism between these 2 oncogenes in tumorigenesis. Regulates cap-dependent protein translation in a mammalian target of rapamycin complex 1 (mTORC1)-independent manner and in parallel to the PI3K-Akt pathway. Mediates survival signaling through phosphorylation of BAD, which induces release of the anti-apoptotic protein Bcl-X(L)/BCL2L1. Promotes cell survival in response to a variety of proliferative signals via positive regulation of the I-kappa-B kinase/NF-kappa-B cascade; this process requires phosphorylation of MAP3K8/COT. Isoform 1 is less active in this respect. Promotes growth factor-independent proliferation by phosphorylation of cell cycle factors such as CDKN1A and CDKN1B. Involved in the positive regulation of chondrocyte survival and autophagy in the epiphyseal growth plate.<ref>PMID:18593906</ref> <ref>PMID:18675992</ref> <ref>PMID:20307683</ref> |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
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| | </div> | | </div> |
| | <div class="pdbe-citations 2iwi" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 2iwi" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Serine/threonine protein kinase 3D structures|Serine/threonine protein kinase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Non-specific serine/threonine protein kinase]]
| + | [[Category: Amos A]] |
| - | [[Category: Amos, A]] | + | [[Category: Arrowsmith C]] |
| - | [[Category: Arrowsmith, C]] | + | [[Category: Bullock AN]] |
| - | [[Category: Bullock, A N]] | + | [[Category: Bunkoczi G]] |
| - | [[Category: Bunkoczi, G]] | + | [[Category: Debreczeni JE]] |
| - | [[Category: Debreczeni, J E]] | + | [[Category: Edwards A]] |
| - | [[Category: Delft, F von]]
| + | [[Category: Fedorov O]] |
| - | [[Category: Edwards, A]] | + | [[Category: Gorrec F]] |
| - | [[Category: Fedorov, O]] | + | [[Category: Knapp S]] |
| - | [[Category: Gorrec, F]] | + | [[Category: Niesen F]] |
| - | [[Category: Knapp, S]] | + | [[Category: Papagrigoriou E]] |
| - | [[Category: Niesen, F]] | + | [[Category: Pike ACW]] |
| - | [[Category: Papagrigoriou, E]] | + | [[Category: Russo S]] |
| - | [[Category: Pike, A C.W]] | + | [[Category: Sobott F]] |
| - | [[Category: Russo, S]] | + | [[Category: Sundstrom M]] |
| - | [[Category: Sobott, F]] | + | [[Category: Turnbull A]] |
| - | [[Category: Sundstrom, M]] | + | [[Category: Ugochukwu E]] |
| - | [[Category: Turnbull, A]] | + | [[Category: Weigelt J]] |
| - | [[Category: Ugochukwu, E]] | + | [[Category: Von Delft F]] |
| - | [[Category: Weigelt, J]] | + | |
| - | [[Category: Atp-binding]] | + | |
| - | [[Category: Cancer]]
| + | |
| - | [[Category: Kinase]]
| + | |
| - | [[Category: Leukemia]]
| + | |
| - | [[Category: Nucleotide-binding]]
| + | |
| - | [[Category: Phosphorylation]]
| + | |
| - | [[Category: Pim2]]
| + | |
| - | [[Category: Proto-oncogene]]
| + | |
| - | [[Category: Serine/threonine-protein kinase]]
| + | |
| - | [[Category: Transferase]]
| + | |
| Structural highlights
Function
PIM2_HUMAN Proto-oncogene with serine/threonine kinase activity involved in cell survival and cell proliferation. Exerts its oncogenic activity through: the regulation of MYC transcriptional activity, the regulation of cell cycle progression, the regulation of cap-dependent protein translation and through survival signaling by phosphorylation of a pro-apoptotic protein, BAD. Phosphorylation of MYC leads to an increase of MYC protein stability and thereby an increase transcriptional activity. The stabilization of MYC exerted by PIM2 might explain partly the strong synergism between these 2 oncogenes in tumorigenesis. Regulates cap-dependent protein translation in a mammalian target of rapamycin complex 1 (mTORC1)-independent manner and in parallel to the PI3K-Akt pathway. Mediates survival signaling through phosphorylation of BAD, which induces release of the anti-apoptotic protein Bcl-X(L)/BCL2L1. Promotes cell survival in response to a variety of proliferative signals via positive regulation of the I-kappa-B kinase/NF-kappa-B cascade; this process requires phosphorylation of MAP3K8/COT. Isoform 1 is less active in this respect. Promotes growth factor-independent proliferation by phosphorylation of cell cycle factors such as CDKN1A and CDKN1B. Involved in the positive regulation of chondrocyte survival and autophagy in the epiphyseal growth plate.[1] [2] [3]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
BACKGROUND: The serine/threonine kinase PIM2 is highly expressed in human leukemia and lymphomas and has been shown to positively regulate survival and proliferation of tumor cells. Its diverse ATP site makes PIM2 a promising target for the development of anticancer agents. To date our knowledge of catalytic domain structures of the PIM kinase family is limited to PIM1 which has been extensively studied and which shares about 50% sequence identity with PIM2. PRINCIPAL FINDINGS: Here we determined the crystal structure of PIM2 in complex with an organoruthenium complex (inhibition in sub-nanomolar level). Due to its extraordinary shape complementarity this stable organometallic compound is a highly potent inhibitor of PIM kinases. SIGNIFICANCE: The structure of PIM2 revealed several differences to PIM1 which may be explored further to generate isoform selective inhibitors. It has also demonstrated how an organometallic inhibitor can be adapted to the binding site of protein kinases to generate highly potent inhibitors. ENHANCED VERSION: This article can also be viewed as an enhanced version in which the text of the article is integrated with interactive 3D representations and animated transitions. Please note that a web plugin is required to access this enhanced functionality. Instructions for the installation and use of the web plugin are available in Text S1.
Crystal structure of the PIM2 kinase in complex with an organoruthenium inhibitor.,Bullock AN, Russo S, Amos A, Pagano N, Bregman H, Debreczeni JE, Lee WH, von Delft F, Meggers E, Knapp S PLoS One. 2009 Oct 20;4(10):e7112. PMID:19841674[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Morishita D, Katayama R, Sekimizu K, Tsuruo T, Fujita N. Pim kinases promote cell cycle progression by phosphorylating and down-regulating p27Kip1 at the transcriptional and posttranscriptional levels. Cancer Res. 2008 Jul 1;68(13):5076-85. doi: 10.1158/0008-5472.CAN-08-0634. PMID:18593906 doi:10.1158/0008-5472.CAN-08-0634
- ↑ Gong J, Wang J, Ren K, Liu C, Li B, Shi Y. Serine/threonine kinase Pim-2 promotes liver tumorigenesis induction through mediating survival and preventing apoptosis of liver cell. J Surg Res. 2009 May 1;153(1):17-22. doi: 10.1016/j.jss.2008.03.033. Epub 2008, Apr 22. PMID:18675992 doi:http://dx.doi.org/10.1016/j.jss.2008.03.033
- ↑ Wang Z, Zhang Y, Gu JJ, Davitt C, Reeves R, Magnuson NS. Pim-2 phosphorylation of p21(Cip1/WAF1) enhances its stability and inhibits cell proliferation in HCT116 cells. Int J Biochem Cell Biol. 2010 Jun;42(6):1030-8. doi:, 10.1016/j.biocel.2010.03.012. Epub 2010 Mar 20. PMID:20307683 doi:http://dx.doi.org/10.1016/j.biocel.2010.03.012
- ↑ Bullock AN, Russo S, Amos A, Pagano N, Bregman H, Debreczeni JE, Lee WH, von Delft F, Meggers E, Knapp S. Crystal structure of the PIM2 kinase in complex with an organoruthenium inhibitor. PLoS One. 2009 Oct 20;4(10):e7112. PMID:19841674 doi:10.1371/journal.pone.0007112
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