5na0: Difference between revisions
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<StructureSection load='5na0' size='340' side='right'caption='[[5na0]], [[Resolution|resolution]] 2.90Å' scene=''> | <StructureSection load='5na0' size='340' side='right'caption='[[5na0]], [[Resolution|resolution]] 2.90Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[5na0]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5NA0 OCA]. For a <b>guided tour on the structure components</b> use [ | <table><tr><td colspan='2'>[[5na0]] 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=5NA0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5NA0 FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=8QZ:~{N}-[3,5-diethyl-1-[2-[2-(2-methoxyethoxy)ethoxy]ethyl]pyrazol-4-yl]-2-[[2-methoxy-4-[4-(2-methoxyethanoyl)piperazin-1-yl]phenyl]amino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide'>8QZ</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]] 2.9Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=8QZ:~{N}-[3,5-diethyl-1-[2-[2-(2-methoxyethoxy)ethoxy]ethyl]pyrazol-4-yl]-2-[[2-methoxy-4-[4-(2-methoxyethanoyl)piperazin-1-yl]phenyl]amino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide'>8QZ</scene>, <scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</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=5na0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5na0 OCA], [https://pdbe.org/5na0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5na0 RCSB], [https://www.ebi.ac.uk/pdbsum/5na0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5na0 ProSAT]</span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | |||
</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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__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Homo sapiens]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Buijsman | [[Category: Buijsman RC]] | ||
[[Category: Uitdehaag J]] | |||
[[Category: Uitdehaag | [[Category: Willemsen-Seegers N]] | ||
[[Category: Willemsen-Seegers | [[Category: Zaman GJR]] | ||
[[Category: Zaman | [[Category: De Man J]] | ||
[[Category: | |||
Latest revision as of 15:41, 15 November 2023
TTK kinase domain in complex with a PEG-linked pyrimido-indolizineTTK kinase domain in complex with a PEG-linked pyrimido-indolizine
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 PubMedThe protein kinase threonine tyrosine kinase (TTK; also known as Mps1) is a critical component of the spindle assembly checkpoint and a promising drug target for the treatment of aggressive cancers, such as triple negative breast cancer. While the first TTK inhibitors have entered clinical trials, little is known about how the inhibition of TTK with small-molecule compounds affects cellular activity. We studied the selective TTK inhibitor NTRC 0066-0, which was developed in our own laboratory, together with 11 TTK inhibitors developed by other companies, including Mps-BAY2b, BAY 1161909, BAY 1217389 (Bayer), TC-Mps1-12 (Shionogi), and MPI-0479605 (Myrexis). Parallel testing shows that the cellular activity of these TTK inhibitors correlates with their binding affinity to TTK and, more strongly, with target residence time. TTK inhibitors are therefore an example where target residence time determines activity in in vitro cellular assays. X-ray structures and thermal stability experiments reveal that the most potent compounds induce a shift of the glycine-rich loop as a result of binding to the catalytic lysine at position 553. This "lysine trap" disrupts the catalytic machinery. Based on these insights, we developed TTK inhibitors, based on a (5,6-dihydro)pyrimido[4,5-e]indolizine scaffold, with longer target residence times, which further exploit an allosteric pocket surrounding Lys553. Their binding mode is new for kinase inhibitors and can be classified as hybrid Type I/Type III. These inhibitors have very potent anti-proliferative activity that rivals classic cytotoxic therapy. Our findings will open up new avenues for more applications for TTK inhibitors in cancer treatment. Target Residence Time-Guided Optimization on TTK Kinase Results in Inhibitors with Potent Anti-Proliferative Activity.,Uitdehaag JCM, de Man J, Willemsen-Seegers N, Prinsen MBW, Libouban MAA, Sterrenburg JG, de Wit JJP, de Vetter JRF, de Roos JADM, Buijsman RC, Zaman GJR J Mol Biol. 2017 Jul 7;429(14):2211-2230. doi: 10.1016/j.jmb.2017.05.014. Epub, 2017 May 21. PMID:28539250[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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