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==TTK in Complex with Inhibitor==
==TTK in Complex with Inhibitor==
<StructureSection load='6b4w' size='340' side='right' caption='[[6b4w]], [[Resolution|resolution]] 2.90&Aring;' scene=''>
<StructureSection load='6b4w' size='340' side='right'caption='[[6b4w]], [[Resolution|resolution]] 2.90&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[6b4w]] 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=6B4W OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6B4W FirstGlance]. <br>
<table><tr><td colspan='2'>[[6b4w]] 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=6B4W OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6B4W FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CAC:CACODYLATE+ION'>CAC</scene>, <scene name='pdbligand=CQ7:4-{[4-(cyclopentyloxy)-5-(2-methyl-1,3-benzoxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino}-3-methoxy-N-methylbenzamide'>CQ7</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]] 2.9&#8491;</td></tr>
<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>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CAC:CACODYLATE+ION'>CAC</scene>, <scene name='pdbligand=CQ7:4-{[4-(cyclopentyloxy)-5-(2-methyl-1,3-benzoxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino}-3-methoxy-N-methylbenzamide'>CQ7</scene></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='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6b4w FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6b4w OCA], [https://pdbe.org/6b4w PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6b4w RCSB], [https://www.ebi.ac.uk/pdbsum/6b4w PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6b4w ProSAT]</span></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=6b4w FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6b4w OCA], [http://pdbe.org/6b4w PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6b4w RCSB], [http://www.ebi.ac.uk/pdbsum/6b4w PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6b4w 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;">
== Publication Abstract from PubMed ==
Triple negative breast cancer (TNBC) remains a serious unmet medical need with discouragingly high relapse rates. We report here the synthesis and structure-activity relationship (SAR) of a novel series of 2,4,5-trisubstituted-7H-pyrrolo[2,3-d]pyrimidines with potent activity against TNBC tumor cell lines. These compounds were discovered from a TNBC phenotypic screen and possess a unique dual inhibition profile targeting TTK (mitotic exit) and CLK2 (mRNA splicing). Design and optimization, driven with a TNBC tumor cell assay, identified potent and selective compounds with favorable in vitro and in vivo activity profiles and good iv PK properties. This cell-based driven SAR produced compounds with strong single agent in vivo efficacy in multiple TNBC xenograft models without significant body weight loss. These data supported the nomination of CC-671 into IND-enabling studies as a single agent TNBC therapy.


The discovery of a dual TTK protein kinase/ CDC2-like kinase (CLK2) inhibitor for the treatment of triple negative breast cancer initiated from a phenotypic screen.,Riggs JR, Nagy M, Elsner J, Erdman P, Cashion D, Robinson D, Harris R, Huang D, Tehrani L, Deyanat-Yazdi G, Narla RK, Peng X, Tran T, Barnes L, Miller T, Katz J, Tang Y, Chen M, Moghaddam MF, Bahmanyar S, Pagarigan B, Delker SL, LeBrun L, Chamberlain PP, Calabrese A, Canan SS, Leftheris K, Zhu D, Boylan JF J Med Chem. 2017 Oct 9. doi: 10.1021/acs.jmedchem.7b01223. PMID:28991472<ref>PMID:28991472</ref>
==See Also==
 
*[[Dual specificity protein kinase 3D structures|Dual specificity protein kinase 3D structures]]
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6b4w" style="background-color:#fffaf0;"></div>
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Dual-specificity kinase]]
[[Category: Homo sapiens]]
[[Category: Human]]
[[Category: Large Structures]]
[[Category: Chamberlain, P P]]
[[Category: Chamberlain PP]]
[[Category: Delker, S]]
[[Category: Delker S]]
[[Category: Protein kinase]]
[[Category: Signaling protein]]

Latest revision as of 17:20, 13 March 2024

TTK in Complex with InhibitorTTK in Complex with Inhibitor

Structural highlights

6b4w is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.9Å
Ligands:,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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]

See Also

References

  1. ↑ 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

6b4w, resolution 2.90Å

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