3w1f

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==Crystal structure of Human MPS1 catalytic domain in complex with 5-(5-ethoxy-6-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-3-yl)-2-methylbenzenesulfonamide==
==Crystal structure of Human MPS1 catalytic domain in complex with 5-(5-ethoxy-6-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-3-yl)-2-methylbenzenesulfonamide==
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<StructureSection load='3w1f' size='340' side='right' caption='[[3w1f]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
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<StructureSection load='3w1f' size='340' side='right'caption='[[3w1f]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[3w1f]] 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=3W1F OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3W1F FirstGlance]. <br>
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<table><tr><td colspan='2'>[[3w1f]] 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=3W1F OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3W1F FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1O5:5-[5-ETHOXY-6-(1-METHYL-1H-PYRAZOL-4-YL)-1H-INDAZOL-3-YL]-2-METHYLBENZENESULFONAMIDE'>1O5</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.7&#8491;</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3vqu|3vqu]]</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1O5:5-[5-ETHOXY-6-(1-METHYL-1H-PYRAZOL-4-YL)-1H-INDAZOL-3-YL]-2-METHYLBENZENESULFONAMIDE'>1O5</scene></td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">TTK, MPS1, MPS1L1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3w1f FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3w1f OCA], [https://pdbe.org/3w1f PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3w1f RCSB], [https://www.ebi.ac.uk/pdbsum/3w1f PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3w1f ProSAT]</span></td></tr>
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<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>
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<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=3w1f FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3w1f OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3w1f RCSB], [http://www.ebi.ac.uk/pdbsum/3w1f PDBsum]</span></td></tr>
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</table>
</table>
== Function ==
== Function ==
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[[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>
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[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>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Monopolar spindle 1 (Mps1) is essential for centrosome duplication, the spindle assembly check point, and the maintenance of chromosomal instability. Mps1 is highly expressed in cancer cells, and its expression levels correlate with the histological grades of cancers. Thus, selective Mps1 inhibitors offer an attractive opportunity for the development of novel cancer therapies. To design novel Mps1 inhibitors, we utilized the pan-kinase inhibitor anthrapyrazolone (4, SP600125) and its crystal structure bound to JNK1. Our design efforts led to the identification of indazole-based lead 6 with an Mps1 IC50 value of 498 nM. Optimization of the 3- and 6-positions on the indazole core of 6 resulted in 23c with improved Mps1 activity (IC50 = 3.06 nM). Finally, application of structure-based design using the X-ray structure of 23d bound to Mps1 culminated in the discovery of 32a and 32b with improved potency for cellular Mps1 and A549 lung cancer cells. Moreover, 32a and 32b exhibited reasonable selectivities over 120 and 166 kinases, respectively.
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Indazole-Based Potent and Cell-Active Mps1 Kinase Inhibitors: Rational Design from Pan-Kinase Inhibitor Anthrapyrazolone (SP600125).,Kusakabe K, Ide N, Daigo Y, Tachibana Y, Itoh T, Yamamoto T, Hashizume H, Hato Y, Higashino K, Okano Y, Sato Y, Inoue M, Iguchi M, Kanazawa T, Ishioka Y, Dohi K, Kido Y, Sakamoto S, Yasuo K, Maeda M, Higaki M, Ueda K, Yoshizawa H, Baba Y, Shiota T, Murai H, Nakamura Y J Med Chem. 2013 Jun 13;56(11):4343-56. doi: 10.1021/jm4000215. Epub 2013 May 24. PMID:23634759<ref>PMID:23634759</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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==See Also==
==See Also==
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*[[Dual specificity protein kinase|Dual specificity protein kinase]]
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*[[Dual specificity protein kinase 3D structures|Dual specificity protein kinase 3D structures]]
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Dual-specificity kinase]]
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[[Category: Homo sapiens]]
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[[Category: Human]]
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[[Category: Large Structures]]
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[[Category: Baba, Y]]
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[[Category: Baba Y]]
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[[Category: Daigo, Y]]
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[[Category: Daigo Y]]
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[[Category: Dohi, K]]
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[[Category: Dohi K]]
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[[Category: Hashizume, H]]
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[[Category: Hashizume H]]
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[[Category: Hato, Y]]
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[[Category: Hato Y]]
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[[Category: Higaki, M]]
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[[Category: Higaki M]]
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[[Category: Higashino, K]]
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[[Category: Higashino K]]
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[[Category: Ide, N]]
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[[Category: Ide N]]
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[[Category: Iguchi, M]]
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[[Category: Iguchi M]]
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[[Category: Inoue, M]]
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[[Category: Inoue M]]
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[[Category: Ishioka, Y]]
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[[Category: Ishioka Y]]
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[[Category: Itoh, T]]
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[[Category: Itoh T]]
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[[Category: Kanazawa, T]]
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[[Category: Kanazawa T]]
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[[Category: Kido, Y]]
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[[Category: Kido Y]]
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[[Category: Kusakabe, K]]
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[[Category: Kusakabe K]]
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[[Category: Maeda, M]]
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[[Category: Maeda M]]
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[[Category: Murai, H]]
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[[Category: Murai H]]
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[[Category: Nakamura, Y]]
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[[Category: Nakamura Y]]
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[[Category: Okano, Y]]
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[[Category: Okano Y]]
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[[Category: Sakamoto, S]]
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[[Category: Sakamoto S]]
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[[Category: Sato, Y]]
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[[Category: Sato Y]]
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[[Category: Shiota, T]]
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[[Category: Shiota T]]
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[[Category: Tachibana, Y]]
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[[Category: Tachibana Y]]
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[[Category: Ueda, K]]
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[[Category: Ueda K]]
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[[Category: Yamamoto, T]]
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[[Category: Yamamoto T]]
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[[Category: Yasuo, K]]
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[[Category: Yasuo K]]
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[[Category: Yoshizawa, H]]
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[[Category: Yoshizawa H]]
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[[Category: Kinase]]
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[[Category: Serine/threonine-protein kinase]]
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[[Category: Transferase-transferase inhibitor complex]]
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Current revision

Crystal structure of Human MPS1 catalytic domain in complex with 5-(5-ethoxy-6-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-3-yl)-2-methylbenzenesulfonamide

PDB ID 3w1f

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