View source for 5n87


==TTK kinase domain in complex with NTRC 0066-0==
<StructureSection load='5n87' size='340' side='right'caption='[[5n87]], [[Resolution|resolution]] 2.29&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5n87]] 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=5N87 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5N87 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.29&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=N66:~{N}-(2,6-diethylphenyl)-2-[[2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide'>N66</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=PGF:2,5,8,11-TETRAOXATRIDECANE'>PGF</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=5n87 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5n87 OCA], [https://pdbe.org/5n87 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5n87 RCSB], [https://www.ebi.ac.uk/pdbsum/5n87 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5n87 ProSAT]</span></td></tr>
</table>
== 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;">
== Publication Abstract from PubMed ==
The 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<ref>PMID:28539250</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5n87" style="background-color:#fffaf0;"></div>

==See Also==
*[[Dual specificity protein kinase 3D structures|Dual specificity protein kinase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Buijsman RC]]
[[Category: Sterrenburg JG]]
[[Category: Uitdehaag J]]
[[Category: Willemsen-Seegers N]]
[[Category: Zaman GJR]]
[[Category: De Man J]]