|
|
| (One intermediate revision not shown.) |
| Line 3: |
Line 3: |
| | <StructureSection load='5m5a' size='340' side='right'caption='[[5m5a]], [[Resolution|resolution]] 1.90Å' scene=''> | | <StructureSection load='5m5a' size='340' side='right'caption='[[5m5a]], [[Resolution|resolution]] 1.90Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5m5a]] 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=5M5A OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5M5A FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5m5a]] 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=5M5A OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5M5A FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=KSA:K-252A'>KSA</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</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]] 1.9Å</td></tr> |
| - | <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>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=KSA:K-252A'>KSA</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></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=5m5a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5m5a OCA], [http://pdbe.org/5m5a PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5m5a RCSB], [http://www.ebi.ac.uk/pdbsum/5m5a PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5m5a ProSAT]</span></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=5m5a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5m5a OCA], [https://pdbe.org/5m5a PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5m5a RCSB], [https://www.ebi.ac.uk/pdbsum/5m5a PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5m5a ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[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. | + | [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 == |
| - | [[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> | + | [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 ==
| + | |
| - | Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.
| + | |
| - | | + | |
| - | The target landscape of clinical kinase drugs.,Klaeger S, Heinzlmeir S, Wilhelm M, Polzer H, Vick B, Koenig PA, Reinecke M, Ruprecht B, Petzoldt S, Meng C, Zecha J, Reiter K, Qiao H, Helm D, Koch H, Schoof M, Canevari G, Casale E, Depaolini SR, Feuchtinger A, Wu Z, Schmidt T, Rueckert L, Becker W, Huenges J, Garz AK, Gohlke BO, Zolg DP, Kayser G, Vooder T, Preissner R, Hahne H, Tonisson N, Kramer K, Gotze K, Bassermann F, Schlegl J, Ehrlich HC, Aiche S, Walch A, Greif PA, Schneider S, Felder ER, Ruland J, Medard G, Jeremias I, Spiekermann K, Kuster B Science. 2017 Dec 1;358(6367). pii: 358/6367/eaan4368. doi:, 10.1126/science.aan4368. PMID:29191878<ref>PMID:29191878</ref>
| + | |
| - | | + | |
| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
| + | |
| - | </div>
| + | |
| - | <div class="pdbe-citations 5m5a" style="background-color:#fffaf0;"></div>
| + | |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Canevari, G]] | + | [[Category: Canevari G]] |
| - | [[Category: Casale, E]] | + | [[Category: Casale E]] |
| - | [[Category: Depaolini, S Re]]
| + | [[Category: Felder E]] |
| - | [[Category: Felder, E]] | + | [[Category: Heinzlmeir S]] |
| - | [[Category: Heinzlmeir, S]] | + | [[Category: Kuster B]] |
| - | [[Category: Kuster, B]] | + | [[Category: Re Depaolini S]] |
| - | [[Category: Complex]] | + | |
| - | [[Category: Inhibitor]]
| + | |
| - | [[Category: Kinase]]
| + | |
| - | [[Category: Transferase]]
| + | |
| Structural highlights
Disease
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
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.[1] [2] [3] [4] [5] [6]
References
- ↑ Seong HA, Gil M, Kim KT, Kim SJ, Ha H. Phosphorylation of a novel zinc-finger-like protein, ZPR9, by murine protein serine/threonine kinase 38 (MPK38). Biochem J. 2002 Feb 1;361(Pt 3):597-604. PMID:11802789
- ↑ Davezac N, Baldin V, Blot J, Ducommun B, Tassan JP. Human pEg3 kinase associates with and phosphorylates CDC25B phosphatase: a potential role for pEg3 in cell cycle regulation. Oncogene. 2002 Oct 31;21(50):7630-41. PMID:12400006 doi:10.1038/sj.onc.1205870
- ↑ Vulsteke V, Beullens M, Boudrez A, Keppens S, Van Eynde A, Rider MH, Stalmans W, Bollen M. Inhibition of spliceosome assembly by the cell cycle-regulated protein kinase MELK and involvement of splicing factor NIPP1. J Biol Chem. 2004 Mar 5;279(10):8642-7. Epub 2003 Dec 29. PMID:14699119 doi:10.1074/jbc.M311466200
- ↑ Mirey G, Chartrain I, Froment C, Quaranta M, Bouche JP, Monsarrat B, Tassan JP, Ducommun B. CDC25B phosphorylated by pEg3 localizes to the centrosome and the spindle poles at mitosis. Cell Cycle. 2005 Jun;4(6):806-11. Epub 2005 Jun 5. PMID:15908796
- ↑ Beullens M, Vancauwenbergh S, Morrice N, Derua R, Ceulemans H, Waelkens E, Bollen M. Substrate specificity and activity regulation of protein kinase MELK. J Biol Chem. 2005 Dec 2;280(48):40003-11. Epub 2005 Oct 10. PMID:16216881 doi:10.1074/jbc.M507274200
- ↑ Lin ML, Park JH, Nishidate T, Nakamura Y, Katagiri T. Involvement of maternal embryonic leucine zipper kinase (MELK) in mammary carcinogenesis through interaction with Bcl-G, a pro-apoptotic member of the Bcl-2 family. Breast Cancer Res. 2007;9(1):R17. PMID:17280616 doi:10.1186/bcr1650
|
