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| | ==Crystal structure of human Mps1 (TTK) in complex with Reversine== | | ==Crystal structure of human Mps1 (TTK) in complex with Reversine== |
| - | <StructureSection load='5ljj' size='340' side='right' caption='[[5ljj]], [[Resolution|resolution]] 3.00Å' scene=''> | + | <StructureSection load='5ljj' size='340' side='right'caption='[[5ljj]], [[Resolution|resolution]] 3.00Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5ljj]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5LJJ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5LJJ FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5ljj]] 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=5LJJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5LJJ FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=AD5:N~6~-CYCLOHEXYL-N~2~-(4-MORPHOLIN-4-YLPHENYL)-9H-PURINE-2,6-DIAMINE'>AD5</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</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]] 3Å</td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Dual-specificity_kinase Dual-specificity kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.12.1 2.7.12.1] </span></td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AD5:N~6~-CYCLOHEXYL-N~2~-(4-MORPHOLIN-4-YLPHENYL)-9H-PURINE-2,6-DIAMINE'>AD5</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</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=5ljj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ljj OCA], [http://pdbe.org/5ljj PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ljj RCSB], [http://www.ebi.ac.uk/pdbsum/5ljj PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ljj 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=5ljj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ljj OCA], [https://pdbe.org/5ljj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ljj RCSB], [https://www.ebi.ac.uk/pdbsum/5ljj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ljj ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/TTK_HUMAN TTK_HUMAN]] Phosphorylates proteins on serine, threonine, and tyrosine. Probably associated with cell proliferation. Essential for chromosome alignment by enhancing AURKB activity (via direct CDCA8 phosphorylation) at the centromere, and for the mitotic checkpoint.<ref>PMID:18243099</ref> | + | [https://www.uniprot.org/uniprot/TTK_HUMAN TTK_HUMAN] Phosphorylates proteins on serine, threonine, and tyrosine. Probably associated with cell proliferation. Essential for chromosome alignment by enhancing AURKB activity (via direct CDCA8 phosphorylation) at the centromere, and for the mitotic checkpoint.<ref>PMID:18243099</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 5ljj" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 5ljj" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Dual specificity protein kinase 3D structures|Dual specificity protein kinase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Dual-specificity kinase]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Hiruma, Y]] | + | [[Category: Large Structures]] |
| - | [[Category: Joosten, R P]] | + | [[Category: Hiruma Y]] |
| - | [[Category: Perrakis, A]] | + | [[Category: Joosten RP]] |
| - | [[Category: Kinase]] | + | [[Category: Perrakis A]] |
| - | [[Category: Mitosis checkpoint]]
| + | |
| - | [[Category: Mps1]]
| + | |
| - | [[Category: Reversine]]
| + | |
| - | [[Category: Transferase]]
| + | |
| - | [[Category: Ttk]]
| + | |
| Structural highlights
Function
TTK_HUMAN Phosphorylates proteins on serine, threonine, and tyrosine. Probably associated with cell proliferation. Essential for chromosome alignment by enhancing AURKB activity (via direct CDCA8 phosphorylation) at the centromere, and for the mitotic checkpoint.[1]
Publication Abstract from PubMed
Monopolar spindle 1 (Mps1, also known as TTK) is a protein kinase crucial for ensuring that cell division progresses to anaphase only after all chromosomes are connected to spindle microtubules. Incomplete chromosomal attachment leads to abnormal chromosome counts in the daughter cells (aneuploidy), a condition common in many solid cancers. Therefore Mps1 is an established target in cancer therapy. Mps1 kinase inhibitors include reversine (2-(4-morpholinoanilino)-6-cyclohexylaminopurine), a promiscuous compound first recognized as an inhibitor of the Aurora B mitotic kinase. Here, we present the 3.0-A resolution crystal structure of the Mps1 kinase domain bound to reversine. Structural comparison of reversine bound to Mps1 and Aurora B, indicates a similar binding pose for the purine moiety of reversine making three conserved hydrogen bonds to the protein main chain, explaining the observed promiscuity of this inhibitor. The cyclohexyl and morpholinoaniline moieties of reversine however, have more extensive contacts with the protein in Mps1 than in Aurora B. This is reflected both in structure-based docking energy calculations, and in new experimental data we present here, that both confirm that the affinity of reversine towards Mps1 is about two orders of magnitude higher than towards Aurora B. Thus, our data provides detailed structural understanding of the existing literature that argues reversine inhibits Mps1 more efficiently than Aurora B based on biochemical and in-cell assays. Proteins 2016. (c) 2016 Wiley Periodicals, Inc.
Structural basis of reversine selectivity in inhibiting Mps1 more potently than aurora B kinase.,Hiruma Y, Koch A, Dharadhar S, Joosten RP, Perrakis A Proteins. 2016 Oct 3. doi: 10.1002/prot.25174. PMID:27699881[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Jelluma N, Brenkman AB, van den Broek NJ, Cruijsen CW, van Osch MH, Lens SM, Medema RH, Kops GJ. Mps1 phosphorylates Borealin to control Aurora B activity and chromosome alignment. Cell. 2008 Jan 25;132(2):233-46. doi: 10.1016/j.cell.2007.11.046. PMID:18243099 doi:10.1016/j.cell.2007.11.046
- ↑ Hiruma Y, Koch A, Dharadhar S, Joosten RP, Perrakis A. Structural basis of reversine selectivity in inhibiting Mps1 more potently than aurora B kinase. Proteins. 2016 Oct 3. doi: 10.1002/prot.25174. PMID:27699881 doi:http://dx.doi.org/10.1002/prot.25174
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