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5iha

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Revision as of 07:18, 3 June 2020

MELK in complex with NVS-MELK8F

Structural highlights

5iha is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Related:	5ih8, 5hi9, 5hic
Gene:	MELK, KIAA0175 (HUMAN)
Activity:	Non-specific serine/threonine protein kinase, with EC number 2.7.11.1
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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]

Publication Abstract from PubMed

MELK kinase has been implicated in playing an important role in tumorigenesis. Our previous studies suggested that MELK is involved in the regulation of cell cycle and its genetic depletion leads to growth inhibition in a subset of high MELK-expressing basal-like breast cancer cell lines. Herein we describe the discovery and optimization of novel MELK inhibitors 8a and 8b that recapitulate the cellular effects observed by short hairpin ribonucleic acid (shRNA)-mediated MELK knockdown in cellular models. We also discovered a novel fluorine-induced hydrophobic collapse that locked the ligand in its bioactive conformation and led to a 20-fold gain in potency. These novel pharmacological inhibitors achieved high exposure in vivo and were well tolerated, which may allow further in vivo evaluation.

Toward the Validation of Maternal Embryonic Leucine Zipper Kinase: Discovery, Optimization of Highly Potent and Selective Inhibitors, and Preliminary Biology Insight.,Toure BB, Giraldes J, Smith T, Sprague ER, Wang Y, Mathieu S, Chen Z, Mishina Y, Feng Y, Yan-Neale Y, Shakya S, Chen D, Meyer M, Puleo D, Brazell JT, Straub C, Sage D, Wright K, Yuan Y, Chen X, Duca J, Kim S, Tian L, Martin E, Hurov K, Shao W J Med Chem. 2016 May 26;59(10):4711-23. doi: 10.1021/acs.jmedchem.6b00052. Epub, 2016 May 17. PMID:27187609^[7]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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
↑ Toure BB, Giraldes J, Smith T, Sprague ER, Wang Y, Mathieu S, Chen Z, Mishina Y, Feng Y, Yan-Neale Y, Shakya S, Chen D, Meyer M, Puleo D, Brazell JT, Straub C, Sage D, Wright K, Yuan Y, Chen X, Duca J, Kim S, Tian L, Martin E, Hurov K, Shao W. Toward the Validation of Maternal Embryonic Leucine Zipper Kinase: Discovery, Optimization of Highly Potent and Selective Inhibitors, and Preliminary Biology Insight. J Med Chem. 2016 May 26;59(10):4711-23. doi: 10.1021/acs.jmedchem.6b00052. Epub, 2016 May 17. PMID:27187609 doi:http://dx.doi.org/10.1021/acs.jmedchem.6b00052

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5iha"

@@ Line 1: / Line 1: @@
 ==MELK in complex with NVS-MELK8F==
-<StructureSection load='5iha' size='340' side='right' caption='[[5iha]], [[Resolution|resolution]] 1.96&Aring;' scene=''>
+<StructureSection load='5iha' size='340' side='right'caption='[[5iha]], [[Resolution|resolution]] 1.96&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5iha]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5IHA OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5IHA FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5iha]] 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=5IHA OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5IHA FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6BE:1-METHYL-4-(4-{4-[3-(2-METHYLPROPOXY)PYRIDIN-4-YL]-1H-PYRAZOL-1-YL}PHENYL)PIPERAZINE'>6BE</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6BE:1-METHYL-4-(4-{4-[3-(2-METHYLPROPOXY)PYRIDIN-4-YL]-1H-PYRAZOL-1-YL}PHENYL)PIPERAZINE'>6BE</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5ih8|5ih8]], [[5hi9|5hi9]], [[5hic|5hic]]</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='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </span></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=5iha FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5iha OCA], [http://pdbe.org/5iha PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5iha RCSB], [http://www.ebi.ac.uk/pdbsum/5iha PDBsum]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5iha FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5iha OCA], [http://pdbe.org/5iha PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5iha RCSB], [http://www.ebi.ac.uk/pdbsum/5iha PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5iha ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 26: / Line 27: @@
 __TOC__
 </StructureSection>
+[[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Non-specific serine/threonine protein kinase]]
 [[Category: Brazell, T]]

5iha

From Proteopedia

Revision as of 07:18, 3 June 2020

MELK in complex with NVS-MELK8F

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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