5kcx

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==Pim-1 kinase in Complex with a Selective N-substituted 7-azaindole Inhibitor==
==Pim-1 kinase in Complex with a Selective N-substituted 7-azaindole Inhibitor==
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<StructureSection load='5kcx' size='340' side='right' caption='[[5kcx]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
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<StructureSection load='5kcx' size='340' side='right'caption='[[5kcx]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[5kcx]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5KCX OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5KCX FirstGlance]. <br>
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<table><tr><td colspan='2'>[[5kcx]] 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=5KCX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5KCX FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6S3:4-chloranyl-1-methyl-2-[4-(4-methylpiperazin-1-yl)phenyl]pyrrolo[2,3-b]pyridine-6-carboxamide'>6S3</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=IMD:IMIDAZOLE'>IMD</scene></td></tr>
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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]] 2.2&#8491;</td></tr>
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<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>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6S3:4-chloranyl-1-methyl-2-[4-(4-methylpiperazin-1-yl)phenyl]pyrrolo[2,3-b]pyridine-6-carboxamide'>6S3</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=IMD:IMIDAZOLE'>IMD</scene></td></tr>
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<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=5kcx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5kcx OCA], [http://pdbe.org/5kcx PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5kcx RCSB], [http://www.ebi.ac.uk/pdbsum/5kcx PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5kcx ProSAT]</span></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=5kcx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5kcx OCA], [https://pdbe.org/5kcx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5kcx RCSB], [https://www.ebi.ac.uk/pdbsum/5kcx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5kcx ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
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[[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>
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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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Novel N-substituted azaindoles have been discovered as PIM1 inhibitors. X-ray structures have played a significant role in orienting the chemistry effort in the initial phase of hit confirmation. Disclosure of an unconventional binding mode for 1 and 2, as demonstrated by X-ray crystallography, is presented and was an important factor in selecting and advancing a lead series.
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Discovery of N-substituted 7-azaindoles as PIM1 kinase inhibitors - Part I.,Barberis C, Moorcroft N, Arendt C, Levit M, Moreno-Mazza S, Batchelor J, Mechin I, Majid T Bioorg Med Chem Lett. 2017 Oct 15;27(20):4730-4734. doi:, 10.1016/j.bmcl.2017.08.069. Epub 2017 Sep 18. PMID:28947155<ref>PMID:28947155</ref>
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==See Also==
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*[[Serine/threonine protein kinase 3D structures|Serine/threonine protein kinase 3D structures]]
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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 5kcx" style="background-color:#fffaf0;"></div>
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== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Non-specific serine/threonine protein kinase]]
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[[Category: Homo sapiens]]
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[[Category: McLean, L R]]
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[[Category: Large Structures]]
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[[Category: Mechin, I]]
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[[Category: McLean LR]]
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[[Category: Wang, R]]
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[[Category: Mechin I]]
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[[Category: Zhang, Y]]
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[[Category: Wang R]]
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[[Category: Complex]]
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[[Category: Zhang Y]]
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[[Category: Inhibitor]]
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[[Category: Kinase]]
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[[Category: Transferase-inhibitor complex]]
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Current revision

Pim-1 kinase in Complex with a Selective N-substituted 7-azaindole Inhibitor

PDB ID 5kcx

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