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3jpv

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{{Seed}}
 
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[[Image:3jpv.jpg|left|200px]]
 
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==Crystal structure of human proto-oncogene serine threonine kinase (PIM1) in complex with a consensus peptide and a pyrrolo[2,3-a]carbazole ligand==
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The line below this paragraph, containing "STRUCTURE_3jpv", creates the "Structure Box" on the page.
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<StructureSection load='3jpv' size='340' side='right'caption='[[3jpv]], [[Resolution|resolution]] 2.35&Aring;' scene=''>
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You may change the PDB parameter (which sets the PDB file loaded into the applet)
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== Structural highlights ==
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or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
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<table><tr><td colspan='2'>[[3jpv]] 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=3JPV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3JPV FirstGlance]. <br>
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or leave the SCENE parameter empty for the default display.
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.35&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1DR:1,10-DIHYDROPYRROLO[2,3-A]CARBAZOLE-3-CARBALDEHYDE'>1DR</scene></td></tr>
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{{STRUCTURE_3jpv| PDB=3jpv | SCENE= }}
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3jpv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3jpv OCA], [https://pdbe.org/3jpv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3jpv RCSB], [https://www.ebi.ac.uk/pdbsum/3jpv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3jpv ProSAT]</span></td></tr>
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</table>
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== Function ==
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[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>
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/jp/3jpv_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</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].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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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.
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===Crystal structure of human proto-oncogene serine threonine kinase (PIM1) in complex with a consensus peptide and a pyrrolo[2,3-a]carbazole ligand===
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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>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 3jpv" style="background-color:#fffaf0;"></div>
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==See Also==
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The line below this paragraph, {{ABSTRACT_PUBMED_19788246}}, adds the Publication Abstract to the page
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*[[Serine/threonine protein kinase 3D structures|Serine/threonine protein kinase 3D structures]]
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(as it appears on PubMed at http://www.pubmed.gov), where 19788246 is the PubMed ID number.
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*[[3D structures of pim-1|3D structures of pim-1]]
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== References ==
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{{ABSTRACT_PUBMED_19788246}}
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<references/>
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__TOC__
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==About this Structure==
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</StructureSection>
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3JPV is a 2 chains structure of sequences 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=3JPV OCA].
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==Reference==
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<ref group="xtra">PMID:19788246</ref><references group="xtra"/>
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[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Non-specific serine/threonine protein kinase]]
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[[Category: Large Structures]]
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[[Category: Akue-Gedu, R.]]
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[[Category: Akue-Gedu R]]
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[[Category: Amizon, F.]]
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[[Category: Amizon F]]
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[[Category: Arrowsmith, C H.]]
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[[Category: Arrowsmith CH]]
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[[Category: Azzaro, S.]]
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[[Category: Azzaro S]]
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[[Category: Bain, J.]]
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[[Category: Bain J]]
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[[Category: Bountra, C.]]
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[[Category: Bountra C]]
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[[Category: Bullock, A N.]]
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[[Category: Bullock AN]]
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[[Category: Cohen, P.]]
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[[Category: Cohen P]]
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[[Category: Delft, F von.]]
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[[Category: Edwards A]]
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[[Category: Edwards, A.]]
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[[Category: Fedorov O]]
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[[Category: Fedorov, O.]]
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[[Category: Filippakopoulos P]]
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[[Category: Filippakopoulos, P.]]
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[[Category: Knapp S]]
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[[Category: Knapp, S.]]
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[[Category: Moreau P]]
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[[Category: Moreau, P.]]
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[[Category: Prudhomme M]]
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[[Category: Prudhomme, M.]]
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[[Category: Rossignol E]]
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[[Category: Rossignol, E.]]
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[[Category: Weigelt J]]
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[[Category: SGC, Structural Genomics Consortium.]]
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[[Category: Von Delft F]]
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[[Category: Weigelt, J.]]
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[[Category: Alternative initiation]]
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[[Category: Atp-binding]]
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[[Category: Cell membrane]]
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[[Category: Cytoplasm]]
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[[Category: Kinase]]
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[[Category: Manganese]]
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[[Category: Membrane]]
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[[Category: Metal-binding]]
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[[Category: Nucleotide-binding]]
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[[Category: Nucleus]]
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[[Category: Oncogene]]
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[[Category: Phosphoprotein]]
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[[Category: Pim1]]
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[[Category: Polymorphism]]
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[[Category: Proto-oncogene]]
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[[Category: Serine-threonine]]
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[[Category: Serine/threonine-protein kinase]]
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[[Category: Sgc]]
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[[Category: Structural genomics consortium]]
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[[Category: Transferase]]
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[[Category: Transferase / transferase inhibitor complex]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Oct 28 13:29:47 2009''
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Current revision

Crystal structure of human proto-oncogene serine threonine kinase (PIM1) in complex with a consensus peptide and a pyrrolo[2,3-a]carbazole ligand

PDB ID 3jpv

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