3umx

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[[Image:3umx.png|left|200px]]
 
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{{STRUCTURE_3umx| PDB=3umx | SCENE= }}
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==Crystal structure of Pim1 kinase in complex with inhibitor (Z)-2-[(1H-indol-3-yl)methylene]-7-(azepan-1-ylmethyl)-6-hydroxybenzofuran-3(2H)-one==
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<StructureSection load='3umx' size='340' side='right'caption='[[3umx]], [[Resolution|resolution]] 2.55&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[3umx]] 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=3UMX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3UMX FirstGlance]. <br>
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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]] 2.55&#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=Q18:(2Z)-7-(AZEPAN-1-YLMETHYL)-6-HYDROXY-2-(1H-INDOL-3-YLMETHYLIDENE)-1-BENZOFURAN-3(2H)-ONE'>Q18</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
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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=3umx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3umx OCA], [https://pdbe.org/3umx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3umx RCSB], [https://www.ebi.ac.uk/pdbsum/3umx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3umx 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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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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The serine/threonine kinase Pim-1 is emerging as a promising target for cancer therapeutics. Much attention has recently been focused on identifying potential Pim-1 inhibitor candidates for the treatment of haematopoietic malignancies. The outcome of a rational drug-design project has recently been reported [Nakano et al. (2012), J. Med. Chem. 55, 5151-5156]. The report described the process of optimization of the structure-activity relationship and detailed from a medicinal chemistry perspective the development of a low-potency and nonselective compound initially identified from in silico screening into a potent, selective and metabolically stable Pim-1 inhibitor. Here, the structures of the initial in silico hits are reported and the noteworthy features of the Pim-1 complex structures are described. A particular focus was placed on the rearrangement of the glycine-rich P-loop region that was observed for one of the initial compounds, (Z)-7-(azepan-1-ylmethyl)-2-[(1H-indol-3-yl)methylidene]-6-hydroxy-1-benzofuran-3 (2H)-one (compound 1), and was also found in all further derivatives. This novel P-loop conformation, which appears to be stabilized by an additional interaction with the beta3 strand located above the binding site, is not usually observed in Pim-1 structures.
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===Crystal structure of Pim1 kinase in complex with inhibitor (Z)-2-[(1H-indol-3-yl)methylene]-7-(azepan-1-ylmethyl)-6-hydroxybenzofuran-3(2H)-one===
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Flexibility of the P-loop of Pim-1 kinase: observation of a novel conformation induced by interaction with an inhibitor.,Parker LJ, Watanabe H, Tsuganezawa K, Tomabechi Y, Handa N, Shirouzu M, Yuki H, Honma T, Ogawa N, Nagano T, Yokoyama S, Tanaka A Acta Crystallogr Sect F Struct Biol Cryst Commun. 2012 Aug 1;68(Pt 8):860-6. Epub, 2012 Jul 31. PMID:22869110<ref>PMID:22869110</ref>
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{{ABSTRACT_PUBMED_22869110}}
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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 3umx" style="background-color:#fffaf0;"></div>
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==About this Structure==
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==See Also==
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[[3umx]] is a 1 chain structure with sequence 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=3UMX OCA].
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*[[Serine/threonine protein kinase 3D structures|Serine/threonine protein kinase 3D structures]]
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*[[3D structures of pim-1|3D structures of pim-1]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
[[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: Handa, N.]]
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[[Category: Handa N]]
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[[Category: Parker, L J.]]
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[[Category: Parker LJ]]
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[[Category: Yokoyama, S.]]
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[[Category: Yokoyama S]]
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[[Category: Kinase]]
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[[Category: Kinase inhibitor]]
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[[Category: P-loop]]
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[[Category: Pim-1]]
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[[Category: Rational drug design]]
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[[Category: Transferase-inhibitor complex]]
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Current revision

Crystal structure of Pim1 kinase in complex with inhibitor (Z)-2-[(1H-indol-3-yl)methylene]-7-(azepan-1-ylmethyl)-6-hydroxybenzofuran-3(2H)-one

PDB ID 3umx

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