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4bky

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Revision as of 14:53, 4 August 2016

Crystal structure of unphosphorylated Maternal Embryonic Leucine zipper Kinase (MELK) in complex with pyrrolopyrazole inhibitor

Structural highlights

4bky 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:	4bkz, 4bl1
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

Maternal Embryonic Leucine zipper Kinase (MELK) is upregulated in several types of tumor, including breast, prostate and brain tumors. Its expression is generally associated with cell survival, cell proliferation and resistance to apoptosis. Therefore, the potential of MELK inhibitors as therapeutic agents is recently attracting considerable interest. Here we report the first structures of MELK in complex with AMP-PNP and with nanomolar inhibitors. Our studies shed some light on the role of MELK UBA domain, provide a characterization of the kinase active site and identify key residues for achieving high potency, laying the groundwork for structure-based drug design efforts.

Structural insight into Maternal Embryonic Leucine zipper Kinase (MELK) conformation and inhibition towards structure-based drug design.,Canevari G, Re Depaolini S, Cucchi U, Bertrand JA, Casale E, Perrera C, Forte B, Carpinelli P, Felder ER Biochemistry. 2013 Aug 5. PMID:23914841^[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
↑ Canevari G, Re Depaolini S, Cucchi U, Bertrand JA, Casale E, Perrera C, Forte B, Carpinelli P, Felder ER. Structural insight into Maternal Embryonic Leucine zipper Kinase (MELK) conformation and inhibition towards structure-based drug design. Biochemistry. 2013 Aug 5. PMID:23914841 doi:10.1021/bi4005864

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/4bky"

@@ Line 1: / Line 1: @@
 ==Crystal structure of unphosphorylated Maternal Embryonic Leucine zipper Kinase (MELK) in complex with pyrrolopyrazole inhibitor==
 <StructureSection load='4bky' size='340' side='right' caption='[[4bky]], [[Resolution|resolution]] 1.83&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4bky]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4BKY OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4BKY FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4bky]] 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=4BKY OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4BKY FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=82B:3-{[(4-BROMO-1-METHYL-1H-PYRROL-2-YL)CARBONYL]AMINO}-N-[(1S)-1-PHENYL-2-(PYRROLIDIN-1-YL)ETHYL]-1,4-DIHYDRO-5H-SPIRO[CYCLOPROPANE-1,6-PYRROLO[3,4-C]PYRAZOLE]-5-CARBOXAMIDE'>82B</scene>, <scene name='pdbligand=UNX:UNKNOWN+ATOM+OR+ION'>UNX</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4bkz|4bkz]], [[4bl1|4bl1]]</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=4bky FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bky OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4bky RCSB], [http://www.ebi.ac.uk/pdbsum/4bky 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=4bky FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bky OCA], [http://pdbe.org/4bky PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4bky RCSB], [http://www.ebi.ac.uk/pdbsum/4bky PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4bky 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 4bky" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Homo sapiens]]
+[[Category: Human]]
 [[Category: Bertrand, J A]]
 [[Category: Canevari, G]]

4bky

From Proteopedia

Revision as of 14:53, 4 August 2016

Crystal structure of unphosphorylated Maternal Embryonic Leucine zipper Kinase (MELK) in complex with pyrrolopyrazole inhibitor

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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