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==Structure of MELK in complex with inhibitors== | ==Structure of MELK in complex with inhibitors== | ||
<StructureSection load='4d2p' size='340' side='right' caption='[[4d2p]], [[Resolution|resolution]] 2.55Å' scene=''> | <StructureSection load='4d2p' size='340' side='right'caption='[[4d2p]], [[Resolution|resolution]] 2.55Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4d2p]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4D2P OCA]. For a <b>guided tour on the structure components</b> use [ | <table><tr><td colspan='2'>[[4d2p]] is a 4 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=4D2P OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4D2P FirstGlance]. <br> | ||
</td></tr><tr id=' | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.55Å</td></tr> | ||
<tr id=' | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6Z7:7-({4-[(3-HYDROXY-5-METHOXYPHENYL)AMINO]BENZOYL}AMINO)-1,2,3,4-TETRAHYDROISOQUINOLINIUM'>6Z7</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=4d2p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4d2p OCA], [https://pdbe.org/4d2p PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4d2p RCSB], [https://www.ebi.ac.uk/pdbsum/4d2p PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4d2p ProSAT]</span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | |||
</table> | </table> | ||
== Disease == | == Disease == | ||
[ | [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 == | ||
[ | [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> | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Fragment-based drug design was successfully applied to maternal embryonic leucine zipper kinase (MELK). A low affinity (160 muM) fragment hit was identified, which bound to the hinge region with an atypical binding mode, and this was optimized using structure-based design into a low-nanomolar and cell-penetrant inhibitor, with a good selectivity profile, suitable for use as a chemical probe for elucidation of MELK biology. | |||
Fragment-based discovery of type I inhibitors of maternal embryonic leucine zipper kinase.,Johnson CN, Berdini V, Beke L, Bonnet P, Brehmer D, Coyle JE, Day PJ, Frederickson M, Freyne EJ, Gilissen RA, Hamlett CC, Howard S, Meerpoel L, McMenamin R, Patel S, Rees DC, Sharff A, Sommen F, Wu T, Linders JT ACS Med Chem Lett. 2014 May 23;6(1):25-30. doi: 10.1021/ml5001245. eCollection, 2015 Jan 8. PMID:25589925<ref>PMID:25589925</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 4d2p" style="background-color:#fffaf0;"></div> | |||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Homo sapiens]] | ||
[[Category: Beke | [[Category: Large Structures]] | ||
[[Category: Berdini | [[Category: Beke L]] | ||
[[Category: Bonnet | [[Category: Berdini V]] | ||
[[Category: Brehmer | [[Category: Bonnet P]] | ||
[[Category: Coyle | [[Category: Brehmer D]] | ||
[[Category: Day | [[Category: Coyle JE]] | ||
[[Category: Frederickson | [[Category: Day PJ]] | ||
[[Category: Freyne | [[Category: Frederickson M]] | ||
[[Category: Gilissen | [[Category: Freyne EJE]] | ||
[[Category: Hamlett | [[Category: Gilissen RAHJ]] | ||
[[Category: Howard | [[Category: Hamlett CCF]] | ||
[[Category: Johnson | [[Category: Howard S]] | ||
[[Category: Linders | [[Category: Johnson CN]] | ||
[[Category: McMenamin | [[Category: Linders JTM]] | ||
[[Category: Meerpoel | [[Category: McMenamin R]] | ||
[[Category: Patel | [[Category: Meerpoel L]] | ||
[[Category: Rees | [[Category: Patel S]] | ||
[[Category: Sharff | [[Category: Rees DC]] | ||
[[Category: Sommen | [[Category: Sharff A]] | ||
[[Category: Wu | [[Category: Sommen F]] | ||
[[Category: Wu T]] | |||
Latest revision as of 14:16, 9 May 2024
Structure of MELK in complex with inhibitorsStructure of MELK in complex with inhibitors
Structural highlights
DiseaseMELK_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. FunctionMELK_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.[1] [2] [3] [4] [5] [6] Publication Abstract from PubMedFragment-based drug design was successfully applied to maternal embryonic leucine zipper kinase (MELK). A low affinity (160 muM) fragment hit was identified, which bound to the hinge region with an atypical binding mode, and this was optimized using structure-based design into a low-nanomolar and cell-penetrant inhibitor, with a good selectivity profile, suitable for use as a chemical probe for elucidation of MELK biology. Fragment-based discovery of type I inhibitors of maternal embryonic leucine zipper kinase.,Johnson CN, Berdini V, Beke L, Bonnet P, Brehmer D, Coyle JE, Day PJ, Frederickson M, Freyne EJ, Gilissen RA, Hamlett CC, Howard S, Meerpoel L, McMenamin R, Patel S, Rees DC, Sharff A, Sommen F, Wu T, Linders JT ACS Med Chem Lett. 2014 May 23;6(1):25-30. doi: 10.1021/ml5001245. eCollection, 2015 Jan 8. PMID:25589925[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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