This old version of Proteopedia is provided for student assignments while the new version is undergoing repairs. Content and edits done in this old version of Proteopedia after March 1, 2026 will eventually be lost when it is retired in about June of 2026.

Apply for new accounts at the new Proteopedia. Your logins will work in both the old and new versions.

4umt

From Proteopedia

(Difference between revisions)

Jump to: navigation, search

Revision as of 01:20, 19 January 2017

Structure of MELK in complex with inhibitors

Structural highlights

4umt is a 1 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Related:	4ump, 4umq, 4umr, 4umu
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

A novel Type II kinase inhibitor chemotype has been identified for maternal embryonic leucine zipper kinase (MELK) using structure-based ligand design. The strategy involved structural characterization of an induced DFG-out pocket by protein-ligand X-ray crystallography and incorporation of a slender linkage capable of bypassing a large gate-keeper residue, thus enabling design of molecules accessing both hinge and induced pocket regions. Optimization of an initial hit led to the identification of a low-nanomolar, cell-penetrant Type II inhibitor suitable for use as a chemical probe for MELK.

Structure-Based Design of Type II Inhibitors Applied to Maternal Embryonic Leucine Zipper Kinase.,Johnson CN, Adelinet C, Berdini V, Beke L, Bonnet P, Brehmer D, Calo F, Coyle JE, Day PJ, Frederickson M, Freyne EJ, Gilissen RA, Hamlett CC, Howard S, Meerpoel L, Mevellec L, McMenamin R, Pasquier E, Patel S, Rees DC, Linders JT ACS Med Chem Lett. 2014 May 23;6(1):31-6. doi: 10.1021/ml5001273. eCollection, 2015 Jan 8. PMID:25589926^[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
↑ Johnson CN, Adelinet C, Berdini V, Beke L, Bonnet P, Brehmer D, Calo F, Coyle JE, Day PJ, Frederickson M, Freyne EJ, Gilissen RA, Hamlett CC, Howard S, Meerpoel L, Mevellec L, McMenamin R, Pasquier E, Patel S, Rees DC, Linders JT. Structure-Based Design of Type II Inhibitors Applied to Maternal Embryonic Leucine Zipper Kinase. ACS Med Chem Lett. 2014 May 23;6(1):31-6. doi: 10.1021/ml5001273. eCollection, 2015 Jan 8. PMID:25589926 doi:http://dx.doi.org/10.1021/ml5001273

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/4umt"

@@ Line 1: / Line 1: @@
 ==Structure of MELK in complex with inhibitors==
 <StructureSection load='4umt' size='340' side='right' caption='[[4umt]], [[Resolution|resolution]] 1.98&Aring;' scene=''>
@@ Line 5: / Line 6: @@
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=47W:1-(4-{[3-(ISOQUINOLIN-7-YL)PROP-2-YN-1-YL]OXY}-2-METHOXYBENZYL)PIPERAZINEDIIUM'>47W</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4ump|4ump]], [[4umq|4umq]], [[4umr|4umr]], [[4umu|4umu]]</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=4umt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4umt OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4umt RCSB], [http://www.ebi.ac.uk/pdbsum/4umt PDBsum]</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=4umt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4umt OCA], [http://pdbe.org/4umt PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4umt RCSB], [http://www.ebi.ac.uk/pdbsum/4umt PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4umt ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 19: / Line 20: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 4umt" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>

4umt

From Proteopedia

Revision as of 01:20, 19 January 2017

Structure of MELK in complex with inhibitors

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

Personal tools

Navigation

Search

Toolbox