5tx3

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==Structure of Maternal Embryonic Leucine Zipper Kinase==
==Structure of Maternal Embryonic Leucine Zipper Kinase==
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<StructureSection load='5tx3' size='340' side='right' caption='[[5tx3]], [[Resolution|resolution]] 2.90&Aring;' scene=''>
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<StructureSection load='5tx3' size='340' side='right'caption='[[5tx3]], [[Resolution|resolution]] 2.90&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[5tx3]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5TX3 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5TX3 FirstGlance]. <br>
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<table><tr><td colspan='2'>[[5tx3]] 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=5TX3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5TX3 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=7MY:7-[(1S)-4-hydroxy-2,3-dihydro-1H-inden-1-yl]-5,5-dimethyl-2-({3-[(pyrrolidin-1-yl)methyl]phenyl}amino)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one'>7MY</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]] 2.9&#8491;</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5tvt|5tvt]], [[5twl|5twl]], [[5twy|5twy]], [[5twu|5twu]], [[5twz|5twz]]</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=7MY:7-[(1S)-4-hydroxy-2,3-dihydro-1H-inden-1-yl]-5,5-dimethyl-2-({3-[(pyrrolidin-1-yl)methyl]phenyl}amino)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one'>7MY</scene></td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MELK, KIAA0175 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=5tx3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5tx3 OCA], [https://pdbe.org/5tx3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5tx3 RCSB], [https://www.ebi.ac.uk/pdbsum/5tx3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5tx3 ProSAT]</span></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=5tx3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5tx3 OCA], [http://pdbe.org/5tx3 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5tx3 RCSB], [http://www.ebi.ac.uk/pdbsum/5tx3 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5tx3 ProSAT]</span></td></tr>
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</table>
</table>
== Disease ==
== Disease ==
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[[http://www.uniprot.org/uniprot/MELK_HUMAN MELK_HUMAN]] Note=Defects in MELK are associated with some cancers, such as brain or breast cancers. Expression is dramatically increased in aggressive undifferentiated tumors, correlating with poor patient outcome in breast and brain cancers, suggesting a role in tumor-initiating cells and proliferation via its function in cell proliferation regulation.
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[https://www.uniprot.org/uniprot/MELK_HUMAN MELK_HUMAN] Note=Defects in MELK are associated with some cancers, such as brain or breast cancers. Expression is dramatically increased in aggressive undifferentiated tumors, correlating with poor patient outcome in breast and brain cancers, suggesting a role in tumor-initiating cells and proliferation via its function in cell proliferation regulation.
== Function ==
== Function ==
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[[http://www.uniprot.org/uniprot/MELK_HUMAN MELK_HUMAN]] 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 and carcinogenesis. Required for proliferation of embryonic and postnatal multipotent neural progenitors. Phosphorylates and inhibits BCL2L14, possibly leading to affect mammary carcinogenesis by mediating inhibition of the pro-apoptotic function of 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:11802789</ref> <ref>PMID:12400006</ref> <ref>PMID:14699119</ref> <ref>PMID:15908796</ref> <ref>PMID:16216881</ref> <ref>PMID:17280616</ref>
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[https://www.uniprot.org/uniprot/MELK_HUMAN MELK_HUMAN] 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 and carcinogenesis. Required for proliferation of embryonic and postnatal multipotent neural progenitors. Phosphorylates and inhibits BCL2L14, possibly leading to affect mammary carcinogenesis by mediating inhibition of the pro-apoptotic function of 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:11802789</ref> <ref>PMID:12400006</ref> <ref>PMID:14699119</ref> <ref>PMID:15908796</ref> <ref>PMID:16216881</ref> <ref>PMID:17280616</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Thorough preclinical target validation is essential for the success of drug discovery efforts. In this study, we combined chemical and genetic perturbants, including the development of a novel selective maternal embryonic leucine zipper kinase (MELK) inhibitor HTH-01-091, CRISPR/Cas9-mediated MELK knockout, a novel chemical-induced protein degradation strategy, RNA interference and CRISPR interference to validate MELK as a therapeutic target in basal-like breast cancers (BBC). In common culture conditions, we found that small molecule inhibition, genetic deletion, or acute depletion of MELK did not significantly affect cellular growth. This discrepancy to previous findings illuminated selectivity issues of the widely used MELK inhibitor OTSSP167, and potential off-target effects of MELK-targeting short hairpins. The different genetic and chemical tools developed here allow for the identification and validation of any causal roles MELK may play in cancer biology, which will be required to guide future MELK drug discovery efforts. Furthermore, our study provides a general framework for preclinical target validation.
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MELK is not necessary for the proliferation of basal-like breast cancer cells.,Huang HT, Seo HS, Zhang T, Wang Y, Jiang B, Li Q, Buckley DL, Nabet B, Roberts JM, Paulk J, Dastjerdi S, Winter GE, McLauchlan H, Moran J, Bradner JE, Eck MJ, Dhe-Paganon S, Zhao JJ, Gray NS Elife. 2017 Sep 19;6. doi: 10.7554/eLife.26693. PMID:28926338<ref>PMID:28926338</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 5tx3" style="background-color:#fffaf0;"></div>
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== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Human]]
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[[Category: Homo sapiens]]
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[[Category: Dhe-Paganon, S]]
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[[Category: Large Structures]]
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[[Category: Eck, M J]]
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[[Category: Dhe-Paganon S]]
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[[Category: Gray, N S]]
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[[Category: Eck MJ]]
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[[Category: Huang, H T]]
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[[Category: Gray NS]]
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[[Category: Li, Q]]
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[[Category: Huang H-T]]
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[[Category: Seo, H S]]
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[[Category: Li Q]]
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[[Category: Breast cancer]]
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[[Category: Seo H-S]]
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[[Category: Kinase inhibitor]]
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[[Category: Transferase-transferase inhibitor complex]]
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Current revision

Structure of Maternal Embryonic Leucine Zipper Kinase

PDB ID 5tx3

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Proteopedia Page Contributors and Editors (what is this?)

OCA

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