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| | <StructureSection load='4cqg' size='340' side='right'caption='[[4cqg]], [[Resolution|resolution]] 2.57Å' scene=''> | | <StructureSection load='4cqg' size='340' side='right'caption='[[4cqg]], [[Resolution|resolution]] 2.57Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4cqg]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4CQG OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4CQG FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4cqg]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4CQG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4CQG FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=OT5:1-[6-(3,5-DICHLORO-4-HYDROXYPHENYL)-4-({TRANS-4-[(DIMETHYLAMINO)METHYL]CYCLOHEXYL}AMINO)-1,5-NAPHTHYRIDIN-3-YL]ETHANONE'>OT5</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.57Å</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=4cqg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4cqg OCA], [http://pdbe.org/4cqg PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4cqg RCSB], [http://www.ebi.ac.uk/pdbsum/4cqg PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4cqg ProSAT]</span></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=OT5:1-[6-(3,5-DICHLORO-4-HYDROXYPHENYL)-4-({TRANS-4-[(DIMETHYLAMINO)METHYL]CYCLOHEXYL}AMINO)-1,5-NAPHTHYRIDIN-3-YL]ETHANONE'>OT5</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> |
| | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4cqg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4cqg OCA], [https://pdbe.org/4cqg PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4cqg RCSB], [https://www.ebi.ac.uk/pdbsum/4cqg PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4cqg ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/MELK_MOUSE MELK_MOUSE]] Serine/threonine-protein kinase involved in various processes such as cell cycle regulation, self-renewal of stem cells, apoptosis and splicing regulation. Has a broad substrate specificity; phosphorylates BCL2L14, CDC25B, MAP3K5/ASK1 and ZNF622. Acts as an activator of apoptosis by phosphorylating and activating MAP3K5/ASK1. Acts as a regulator of cell cycle, notably by mediating phosphorylation of CDC25B, promoting localization of CDC25B to the centrosome and the spindle poles during mitosis. Plays a key role in cell proliferation. Required for proliferation of embryonic and postnatal multipotent neural progenitors. Phosphorylates and inhibits BCL2L14. Also involved in the inhibition of spliceosome assembly during mitosis by phosphorylating ZNF622, thereby contributing to its redirection to the nucleus. May also play a role in primitive hematopoiesis.<ref>PMID:16061694</ref> <ref>PMID:18948261</ref> | + | [https://www.uniprot.org/uniprot/MELK_MOUSE MELK_MOUSE] Serine/threonine-protein kinase involved in various processes such as cell cycle regulation, self-renewal of stem cells, apoptosis and splicing regulation. Has a broad substrate specificity; phosphorylates BCL2L14, CDC25B, MAP3K5/ASK1 and ZNF622. Acts as an activator of apoptosis by phosphorylating and activating MAP3K5/ASK1. Acts as a regulator of cell cycle, notably by mediating phosphorylation of CDC25B, promoting localization of CDC25B to the centrosome and the spindle poles during mitosis. Plays a key role in cell proliferation. Required for proliferation of embryonic and postnatal multipotent neural progenitors. Phosphorylates and inhibits BCL2L14. Also involved in the inhibition of spliceosome assembly during mitosis by phosphorylating ZNF622, thereby contributing to its redirection to the nucleus. May also play a role in primitive hematopoiesis.<ref>PMID:16061694</ref> <ref>PMID:18948261</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </StructureSection> | | </StructureSection> |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Cho, H S]] | + | [[Category: Mus musculus]] |
| - | [[Category: Cho, Y S]] | + | [[Category: Cho HS]] |
| - | [[Category: Kang, Y J]] | + | [[Category: Cho YS]] |
| - | [[Category: Transferase]] | + | [[Category: Kang YJ]] |
| Structural highlights
Function
MELK_MOUSE Serine/threonine-protein kinase involved in various processes such as cell cycle regulation, self-renewal of stem cells, apoptosis and splicing regulation. Has a broad substrate specificity; phosphorylates BCL2L14, CDC25B, MAP3K5/ASK1 and ZNF622. Acts as an activator of apoptosis by phosphorylating and activating MAP3K5/ASK1. Acts as a regulator of cell cycle, notably by mediating phosphorylation of CDC25B, promoting localization of CDC25B to the centrosome and the spindle poles during mitosis. Plays a key role in cell proliferation. Required for proliferation of embryonic and postnatal multipotent neural progenitors. Phosphorylates and inhibits BCL2L14. Also involved in the inhibition of spliceosome assembly during mitosis by phosphorylating ZNF622, thereby contributing to its redirection to the nucleus. May also play a role in primitive hematopoiesis.[1] [2]
Publication Abstract from PubMed
Murine protein serine/threonine kinase 38 (MPK38), also known as maternal embryonic leucine zipper kinase (MELK), has been associated with various human cancers and plays an important role in the formation of cancer stem cells. OTSSP167, a MELK selective inhibitor, exhibits a strong in vitro activity, conferring an IC50 of 0.41nM and in vivo effect on various human cancer xenograft models. Here, we report the crystal structure of MPK38 (T167E), an active mutant, in complex with OTSSP167 and describe its detailed protein-inhibitor interactions. Comparison with the previous determined structure of MELK bound to the nanomolar inhibitors shows that OTSSP167 effectively fits into the active site, thus offering an opportunity for structure-based development and optimization of MELK inhibitors.
The crystal structure of MPK38 in complex with OTSSP167, an orally administrative MELK selective inhibitor.,Cho YS, Kang Y, Kim K, Cha YJ, Cho HS Biochem Biophys Res Commun. 2014 Apr 25;447(1):7-11. doi:, 10.1016/j.bbrc.2014.03.034. Epub 2014 Mar 18. PMID:24657156[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Nakano I, Paucar AA, Bajpai R, Dougherty JD, Zewail A, Kelly TK, Kim KJ, Ou J, Groszer M, Imura T, Freije WA, Nelson SF, Sofroniew MV, Wu H, Liu X, Terskikh AV, Geschwind DH, Kornblum HI. Maternal embryonic leucine zipper kinase (MELK) regulates multipotent neural progenitor proliferation. J Cell Biol. 2005 Aug 1;170(3):413-27. PMID:16061694 doi:http://dx.doi.org/10.1083/jcb.200412115
- ↑ Jung H, Seong HA, Ha H. Murine protein serine/threonine kinase 38 activates apoptosis signal-regulating kinase 1 via Thr 838 phosphorylation. J Biol Chem. 2008 Dec 12;283(50):34541-53. doi: 10.1074/jbc.M807219200. Epub 2008, Oct 23. PMID:18948261 doi:http://dx.doi.org/10.1074/jbc.M807219200
- ↑ Cho YS, Kang Y, Kim K, Cha YJ, Cho HS. The crystal structure of MPK38 in complex with OTSSP167, an orally administrative MELK selective inhibitor. Biochem Biophys Res Commun. 2014 Apr 25;447(1):7-11. doi:, 10.1016/j.bbrc.2014.03.034. Epub 2014 Mar 18. PMID:24657156 doi:http://dx.doi.org/10.1016/j.bbrc.2014.03.034
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