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| | ==Kinase domain of human Greatwall== | | ==Kinase domain of human Greatwall== |
| - | <StructureSection load='5loh' size='340' side='right' caption='[[5loh]], [[Resolution|resolution]] 3.10Å' scene=''> | + | <StructureSection load='5loh' size='340' side='right'caption='[[5loh]], [[Resolution|resolution]] 3.10Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5loh]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5LOH OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5LOH FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5loh]] is a 2 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=5LOH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5LOH 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=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=STU:STAUROSPORINE'>STU</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]] 3.1Å</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=5loh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5loh OCA], [http://pdbe.org/5loh PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5loh RCSB], [http://www.ebi.ac.uk/pdbsum/5loh PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5loh ProSAT]</span></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=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=STU:STAUROSPORINE'>STU</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=5loh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5loh OCA], [https://pdbe.org/5loh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5loh RCSB], [https://www.ebi.ac.uk/pdbsum/5loh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5loh ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/GWL_HUMAN GWL_HUMAN]] Autosomal thrombocytopenia with normal platelets. The disease is caused by mutations affecting the gene represented in this entry. | + | [https://www.uniprot.org/uniprot/GWL_HUMAN GWL_HUMAN] Autosomal thrombocytopenia with normal platelets. The disease is caused by mutations affecting the gene represented in this entry. |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/GWL_HUMAN GWL_HUMAN]] Serine/threonine kinase that plays a key role in M phase by acting as a regulator of mitosis entry and maintenance. Acts by promoting the inactivation of protein phosphatase 2A (PP2A) during M phase: does not directly inhibit PP2A but acts by mediating phosphorylation and subsequent activation of ARPP19 and ENSA at 'Ser-62' and 'Ser-67', respectively. ARPP19 and ENSA are phosphatase inhibitors that specifically inhibit the PPP2R2D (PR55-delta) subunit of PP2A. Inactivation of PP2A during M phase is essential to keep cyclin-B1-CDK1 activity high. Following DNA damage, it is also involved in checkpoint recovery by being inhibited. Phosphorylates histone protein in vitro; however such activity is unsure in vivo. May be involved in megakaryocyte differentiation.<ref>PMID:12890928</ref> <ref>PMID:19680222</ref> <ref>PMID:19793917</ref> <ref>PMID:20538976</ref> <ref>PMID:20818157</ref> | + | [https://www.uniprot.org/uniprot/GWL_HUMAN GWL_HUMAN] Serine/threonine kinase that plays a key role in M phase by acting as a regulator of mitosis entry and maintenance. Acts by promoting the inactivation of protein phosphatase 2A (PP2A) during M phase: does not directly inhibit PP2A but acts by mediating phosphorylation and subsequent activation of ARPP19 and ENSA at 'Ser-62' and 'Ser-67', respectively. ARPP19 and ENSA are phosphatase inhibitors that specifically inhibit the PPP2R2D (PR55-delta) subunit of PP2A. Inactivation of PP2A during M phase is essential to keep cyclin-B1-CDK1 activity high. Following DNA damage, it is also involved in checkpoint recovery by being inhibited. Phosphorylates histone protein in vitro; however such activity is unsure in vivo. May be involved in megakaryocyte differentiation.<ref>PMID:12890928</ref> <ref>PMID:19680222</ref> <ref>PMID:19793917</ref> <ref>PMID:20538976</ref> <ref>PMID:20818157</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 5loh" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 5loh" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Microtubule-associated serine/threonine kinase|Microtubule-associated serine/threonine kinase]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Oliver, A W]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Pearl, L H]] | + | [[Category: Large Structures]] |
| - | [[Category: Rajasekaran, M B]] | + | [[Category: Oliver AW]] |
| - | [[Category: Inhibitor]] | + | [[Category: Pearl LH]] |
| - | [[Category: Kinase domain]] | + | [[Category: Rajasekaran MB]] |
| - | [[Category: Transferase]]
| + | |
| Structural highlights
Disease
GWL_HUMAN Autosomal thrombocytopenia with normal platelets. The disease is caused by mutations affecting the gene represented in this entry.
Function
GWL_HUMAN Serine/threonine kinase that plays a key role in M phase by acting as a regulator of mitosis entry and maintenance. Acts by promoting the inactivation of protein phosphatase 2A (PP2A) during M phase: does not directly inhibit PP2A but acts by mediating phosphorylation and subsequent activation of ARPP19 and ENSA at 'Ser-62' and 'Ser-67', respectively. ARPP19 and ENSA are phosphatase inhibitors that specifically inhibit the PPP2R2D (PR55-delta) subunit of PP2A. Inactivation of PP2A during M phase is essential to keep cyclin-B1-CDK1 activity high. Following DNA damage, it is also involved in checkpoint recovery by being inhibited. Phosphorylates histone protein in vitro; however such activity is unsure in vivo. May be involved in megakaryocyte differentiation.[1] [2] [3] [4] [5]
Publication Abstract from PubMed
MASTL (microtubule-associated serine/threonine kinase-like), more commonly known as Greatwall (GWL), has been proposed as a novel cancer therapy target. GWL plays a crucial role in mitotic progression, via its known substrates ENSA/ARPP19, which when phosphorylated inactivate PP2A/B55 phosphatase. When over-expressed in breast cancer, GWL induces oncogenic properties such as transformation and invasiveness. Conversely, down-regulation of GWL selectively sensitises tumour cells to chemotherapy. Here we describe the first structure of the GWL minimal kinase domain and development of a small-molecule inhibitor GKI-1 (Greatwall Kinase Inhibitor-1). In vitro, GKI-1 inhibits full-length human GWL, and shows cellular efficacy. Treatment of HeLa cells with GKI-1 reduces ENSA/ARPP19 phosphorylation levels, such that they are comparable to those obtained by siRNA depletion of GWL; resulting in a decrease in mitotic events, mitotic arrest/cell death and cytokinesis failure. Furthermore, GKI-1 will be a useful starting point for the development of more potent and selective GWL inhibitors.
A first generation inhibitor of human Greatwall kinase, enabled by structural and functional characterisation of a minimal kinase domain construct.,Ocasio CA, Rajasekaran MB, Walker S, Le Grand D, Spencer J, Pearl FM, Ward SE, Savic V, Pearl LH, Hochegger H, Oliver AW Oncotarget. 2016 Aug 22. doi: 10.18632/oncotarget.11511. PMID:27563826[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Gandhi MJ, Cummings CL, Drachman JG. FLJ14813 missense mutation: a candidate for autosomal dominant thrombocytopenia on human chromosome 10. Hum Hered. 2003;55(1):66-70. PMID:12890928 doi:http://dx.doi.org/71812
- ↑ Vigneron S, Brioudes E, Burgess A, Labbe JC, Lorca T, Castro A. Greatwall maintains mitosis through regulation of PP2A. EMBO J. 2009 Sep 16;28(18):2786-93. doi: 10.1038/emboj.2009.228. Epub 2009 Aug, 13. PMID:19680222 doi:http://dx.doi.org/10.1038/emboj.2009.228
- ↑ Castilho PV, Williams BC, Mochida S, Zhao Y, Goldberg ML. The M phase kinase Greatwall (Gwl) promotes inactivation of PP2A/B55delta, a phosphatase directed against CDK phosphosites. Mol Biol Cell. 2009 Nov;20(22):4777-89. doi: 10.1091/mbc.E09-07-0643. Epub 2009, Sep 30. PMID:19793917 doi:http://dx.doi.org/10.1091/mbc.E09-07-0643
- ↑ Burgess A, Vigneron S, Brioudes E, Labbe JC, Lorca T, Castro A. Loss of human Greatwall results in G2 arrest and multiple mitotic defects due to deregulation of the cyclin B-Cdc2/PP2A balance. Proc Natl Acad Sci U S A. 2010 Jul 13;107(28):12564-9. doi:, 10.1073/pnas.0914191107. Epub 2010 Jun 10. PMID:20538976 doi:http://dx.doi.org/10.1073/pnas.0914191107
- ↑ Voets E, Wolthuis RM. MASTL is the human orthologue of Greatwall kinase that facilitates mitotic entry, anaphase and cytokinesis. Cell Cycle. 2010 Sep 1;9(17):3591-601. Epub 2010 Sep 29. PMID:20818157 doi:http://dx.doi.org/10.4161/cc.9.17.12832
- ↑ Ocasio CA, Rajasekaran MB, Walker S, Le Grand D, Spencer J, Pearl FM, Ward SE, Savic V, Pearl LH, Hochegger H, Oliver AW. A first generation inhibitor of human Greatwall kinase, enabled by structural and functional characterisation of a minimal kinase domain construct. Oncotarget. 2016 Aug 22. doi: 10.18632/oncotarget.11511. PMID:27563826 doi:http://dx.doi.org/10.18632/oncotarget.11511
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