4as0

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[[Image:4as0.jpg|left|200px]]
 
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{{STRUCTURE_4as0| PDB=4as0 | SCENE= }}
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==Cyclometalated Phthalimides as Protein Kinase Inhibitors==
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<StructureSection load='4as0' size='340' side='right'caption='[[4as0]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[4as0]] 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=4AS0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4AS0 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]] 2.3&#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=RPS:PHTALIMIDE-RUTHENIUM+COMPLEX'>RPS</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=4as0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4as0 OCA], [https://pdbe.org/4as0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4as0 RCSB], [https://www.ebi.ac.uk/pdbsum/4as0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4as0 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 regioselective cyclometalation of 4-(pyridin-2-yl)phthalimide was exploited for the economical design of organometallic protein kinase inhibitors. 4-(Pyridin-2-yl)phthalimide can be prepared from inexpensive 4-bromophthalimide in just three steps including one Pd-catalyzed Stille cross-coupling. The versatility of this new ligand was demonstrated with the synthesis of ruthenium(II) half-sandwich as well as octahedral ruthenium(II) and iridium(III) complexes. The regioselectivity of the C-H activation in the course of the cyclometalation can be influenced by the reaction conditions and the steric demand of the introduced metal complex fragment. The biological activity of this new class of metalated phthalimides was evaluated by profiling two representative members against a large panel of human protein kinases. A cocrystal structure of one metallo-phthalimide with the protein kinase Pim1 confirmed an ATP-competitive binding with the intended hydrogen bonding between the phthalimide moiety and the hinge region of the ATP-binding site.
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===Cyclometalated Phthalimides as Protein Kinase Inhibitors===
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Bioactive cyclometalated phthalimides: design, synthesis and kinase inhibition.,Blanck S, Geisselbrecht Y, Kraling K, Middel S, Mietke T, Harms K, Essen LO, Meggers E Dalton Trans. 2012 Aug 21;41(31):9337-48. Epub 2012 Jun 26. PMID:22733119<ref>PMID:22733119</ref>
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{{ABSTRACT_PUBMED_22733119}}
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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 4as0" style="background-color:#fffaf0;"></div>
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==About this Structure==
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==See Also==
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[[4as0]] 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=4AS0 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: Blanck, S.]]
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[[Category: Blanck S]]
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[[Category: Essen, L O.]]
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[[Category: Essen L-O]]
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[[Category: Geisselbrecht, Y.]]
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[[Category: Geisselbrecht Y]]
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[[Category: Harms, K.]]
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[[Category: Harms K]]
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[[Category: Meggers, E.]]
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[[Category: Meggers E]]
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[[Category: Middel, S.]]
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[[Category: Middel S]]
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[[Category: Mietke, T.]]
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[[Category: Mietke T]]
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[[Category: Kinase inhibitor]]
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[[Category: Octasporine]]
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[[Category: Pim1]]
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[[Category: Ruthenium]]
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[[Category: Transferase]]
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Current revision

Cyclometalated Phthalimides as Protein Kinase Inhibitors

PDB ID 4as0

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