View source for 3jpv


==Crystal structure of human proto-oncogene serine threonine kinase (PIM1) in complex with a consensus peptide and a pyrrolo[2,3-a]carbazole ligand==
<StructureSection load='3jpv' size='340' side='right' caption='[[3jpv]], [[Resolution|resolution]] 2.35&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[3jpv]] 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=3JPV OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3JPV FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1DR:1,10-DIHYDROPYRROLO[2,3-A]CARBAZOLE-3-CARBALDEHYDE'>1DR</scene></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PIM1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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='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=3jpv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3jpv OCA], [http://pdbe.org/3jpv PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3jpv RCSB], [http://www.ebi.ac.uk/pdbsum/3jpv PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3jpv ProSAT]</span></td></tr>
</table>
== Function ==
[[http://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/jp/3jpv_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=3jpv ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Members of the Pim kinase family have been identified as promising targets for the development of antitumor agents. After a screening of pyrrolo[2,3-a]- and [3,2-a]carbazole derivatives toward 66 protein kinases, we identified pyrrolo[2,3-a]carbazole as a new scaffold to design potent Pim kinase inhibitors. In particular, compound 9 was identified as a low nM selective Pim inhibitor. Additionally, several pyrrolo[2,3-a]carbazole derivatives showed selectivity for Pim-1 and Pim-3 over Pim-2. In vitro antiproliferative activities of 9 and 28, the most potent Pim inhibitors identified, were evaluated toward three human solid cancer cell lines (PA1, PC3, and DU145) and one human fibroblast primary culture, revealing IC50 values in the micromolar range. Finally, the crystal structure of Pim-1 complexed with lead compound 9 was determined. The structure revealed a non-ATP mimetic binding mode with no hydrogen bonds formed with the kinase hinge region and explained the selectivity of pyrrolo[2,3-a]carbazole derivatives for Pim kinases.

Synthesis, kinase inhibitory potencies, and in vitro antiproliferative evaluation of new Pim kinase inhibitors.,Akue-Gedu R, Rossignol E, Azzaro S, Knapp S, Filippakopoulos P, Bullock AN, Bain J, Cohen P, Prudhomme M, Anizon F, Moreau P J Med Chem. 2009 Oct 22;52(20):6369-81. PMID:19788246<ref>PMID:19788246</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 3jpv" style="background-color:#fffaf0;"></div>

==See Also==
*[[Proto-oncogene serine/threonine-protein kinase|Proto-oncogene serine/threonine-protein kinase]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Human]]
[[Category: Non-specific serine/threonine protein kinase]]
[[Category: Akue-Gedu, R]]
[[Category: Amizon, F]]
[[Category: Arrowsmith, C H]]
[[Category: Azzaro, S]]
[[Category: Bain, J]]
[[Category: Bountra, C]]
[[Category: Bullock, A N]]
[[Category: Cohen, P]]
[[Category: Delft, F von]]
[[Category: Edwards, A]]
[[Category: Fedorov, O]]
[[Category: Filippakopoulos, P]]
[[Category: Knapp, S]]
[[Category: Moreau, P]]
[[Category: Prudhomme, M]]
[[Category: Rossignol, E]]
[[Category: Structural genomic]]
[[Category: Weigelt, J]]
[[Category: Alternative initiation]]
[[Category: Atp-binding]]
[[Category: Cell membrane]]
[[Category: Kinase]]
[[Category: Manganese]]
[[Category: Membrane]]
[[Category: Metal-binding]]
[[Category: Nucleotide-binding]]
[[Category: Nucleus]]
[[Category: Oncogene]]
[[Category: Phosphoprotein]]
[[Category: Pim1]]
[[Category: Proto-oncogene]]
[[Category: Serine-threonine]]
[[Category: Serine/threonine-protein kinase]]
[[Category: Sgc]]
[[Category: Transferase]]
[[Category: Transferase - transferase inhibitor complex]]