5o91: Difference between revisions
New page: ==Crystal structure of human Mps1 (TTK) C604W mutant in complex with Cpd-5== <StructureSection load='5o91' size='340' side='right' caption='5o91, resolution 3.20Å... |
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==Crystal structure of human Mps1 (TTK) C604W mutant in complex with Cpd-5== | ==Crystal structure of human Mps1 (TTK) C604W mutant in complex with Cpd-5== | ||
<StructureSection load='5o91' size='340' side='right' caption='[[5o91]], [[Resolution|resolution]] 3.20Å' scene=''> | <StructureSection load='5o91' size='340' side='right'caption='[[5o91]], [[Resolution|resolution]] 3.20Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[5o91]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5O91 OCA]. For a <b>guided tour on the structure components</b> use [ | <table><tr><td colspan='2'>[[5o91]] 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=5O91 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5O91 FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=C5N:~{N}-(2,6-diethylphenyl)-8-[[2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino]-1-methyl-4,5-dihydropyrazolo[4,3-h]quinazoline-3-carboxamide'>C5N</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.2Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=C5N:~{N}-(2,6-diethylphenyl)-8-[[2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino]-1-methyl-4,5-dihydropyrazolo[4,3-h]quinazoline-3-carboxamide'>C5N</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'>[ | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5o91 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5o91 OCA], [https://pdbe.org/5o91 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5o91 RCSB], [https://www.ebi.ac.uk/pdbsum/5o91 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5o91 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
[ | [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 5o91" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 5o91" 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: | [[Category: Homo sapiens]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: | [[Category: Hiruma Y]] | ||
[[Category: | [[Category: Joosten RP]] | ||
[[Category: | [[Category: Perrakis A]] | ||
Latest revision as of 12:37, 6 December 2023
Crystal structure of human Mps1 (TTK) C604W mutant in complex with Cpd-5Crystal structure of human Mps1 (TTK) C604W mutant in complex with Cpd-5
Structural highlights
FunctionTTK_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 PubMedMonopolar spindle 1 (Mps1/TTK) is a protein kinase essential in mitotic checkpoint signalling, preventing anaphase until all chromosomes are properly attached to spindle microtubules. Mps1 has emerged as a potential target for cancer therapy, and a variety of compounds have been developed to inhibit its kinase activity. Mutations in the catalytic domain of Mps1 that give rise to inhibitor resistance, but retain catalytic activity and do not display cross-resistance to other Mps1 inhibitors, have been described. Here we characterize the interactions of two such mutants, Mps1 C604Y and C604W, which raise resistance to two closely related compounds, NMS-P715 and its derivative Cpd-5, but not to the well-characterised Mps1 inhibitor, reversine. We show that estimates of the IC50 (employing a novel specific and efficient assay that utilizes a fluorescently labelled substrate) and of the binding affinity (KD) indicate that in both mutants, Cpd-5 should be better tolerated than the closely related NMS-P715. To gain further insight, we determined the crystal structure of the Mps1 kinase mutants bound to Cpd-5 and NMS-P715, and compare the binding modes of Cpd-5, NMS-P715 and reversine. The difference in steric hindrance between Tyr/Trp604 and the trifluoromethoxy moiety of NMS-P715, the methoxy moiety of Cpd-5, and complete absence of such a group in reversine, account for differences we observe in vitro Our analysis enforces the notion that inhibitors targeting Mps1 drug-resistant mutations can emerge as a feasible intervention strategy based on existing scaffolds, if the clinical need arises. Understanding inhibitor resistance in Mps1 kinase through novel biophysical assays and structures.,Hiruma Y, Koch A, Hazraty N, Tsakou F, Medema RH, Joosten RP, Perrakis A J Biol Chem. 2017 Jul 18. pii: jbc.M117.783555. doi: 10.1074/jbc.M117.783555. PMID:28726638[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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