5k00

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<StructureSection load='5k00' size='340' side='right'caption='[[5k00]], [[Resolution|resolution]] 1.77&Aring;' scene=''>
<StructureSection load='5k00' size='340' side='right'caption='[[5k00]], [[Resolution|resolution]] 1.77&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[5k00]] is a 1 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=5K00 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5K00 FirstGlance]. <br>
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<table><tr><td colspan='2'>[[5k00]] 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=5K00 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5K00 FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6PV:4-{2-[(3-METHOXYPHENYL)AMINO]-4-[(PIPERIDIN-4-YL)METHOXY]PYRIMIDIN-5-YL}-N-[2-OXO-2-(PHENYLAMINO)ETHYL]BENZAMIDE'>6PV</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]] 1.77&#8491;</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='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6PV:4-{2-[(3-METHOXYPHENYL)AMINO]-4-[(PIPERIDIN-4-YL)METHOXY]PYRIMIDIN-5-YL}-N-[2-OXO-2-(PHENYLAMINO)ETHYL]BENZAMIDE'>6PV</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5k00 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5k00 OCA], [http://pdbe.org/5k00 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5k00 RCSB], [http://www.ebi.ac.uk/pdbsum/5k00 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5k00 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=5k00 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5k00 OCA], [https://pdbe.org/5k00 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5k00 RCSB], [https://www.ebi.ac.uk/pdbsum/5k00 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5k00 ProSAT]</span></td></tr>
</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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While adding the structural features that are more favored by on-target activity is the more common strategy in selectivity optimization, the opposite strategy of subtracting the structural features that contribute more to off-target activity can also be very effective. Reported here is our successful effort of improving the kinase selectivity of type II maternal embryonic leucine zipper kinase inhibitors by applying these two complementary approaches together, which clearly demonstrates the powerful synergy between them.
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"Addition" and "Subtraction": Selectivity Design for Type II Maternal Embryonic Leucine Zipper Kinase Inhibitors.,Chen X, Giraldes J, Sprague ER, Shakya S, Chen Z, Wang Y, Joud C, Mathieu S, Chen CH, Straub C, Duca J, Hurov K, Yuan Y, Shao W, Toure BB J Med Chem. 2017 Feb 24. doi: 10.1021/acs.jmedchem.7b00033. PMID:28186750<ref>PMID:28186750</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 5k00" 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]]
[[Category: Large Structures]]
[[Category: Large Structures]]
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[[Category: Sprague, E R]]
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[[Category: Sprague ER]]
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[[Category: Kinase uba typeii inhibitor]]
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[[Category: Transferase-transferase inhibitor complex]]
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Current revision

MELK in complex with NVS-MELK5

PDB ID 5k00

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OCA

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