View source for 5ap3


==Naturally Occurring Mutations in the MPS1 Gene Predispose Cells to Kinase Inhibitor Drug Resistance.==
<StructureSection load='5ap3' size='340' side='right'caption='[[5ap3]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5ap3]] 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=5AP3 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5AP3 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=7PE:2-(2-(2-(2-(2-(2-ETHOXYETHOXY)ETHOXY)ETHOXY)ETHOXY)ETHOXY)ETHANOL'>7PE</scene>, <scene name='pdbligand=AU5:9-CYCLOPENTYL-2-[[2-METHOXY-4-[(1-METHYLPIPERIDIN-4-YL)OXY]-PHENYL]AMINO]-7-METHYL-7,9-DIHYDRO-8H-PURIN-8-ONE'>AU5</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene></td></tr>
<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5ap0|5ap0]], [[5ap1|5ap1]], [[5ap2|5ap2]], [[5ap4|5ap4]], [[5ap5|5ap5]], [[5ap6|5ap6]], [[5ap7|5ap7]]</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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5ap3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ap3 OCA], [http://pdbe.org/5ap3 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ap3 RCSB], [http://www.ebi.ac.uk/pdbsum/5ap3 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ap3 ProSAT]</span></td></tr>
</table>
== 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>  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Acquired resistance to therapy is perhaps the greatest challenge to effective clinical management of cancer. With several inhibitors of the mitotic checkpoint kinase MPS1 in preclinical development, we sought to investigate how resistance against these inhibitors may arise so that mitigation or bypass strategies could be addressed as early as possible. Toward this end, we modeled acquired resistance to the MPS1 inhibitors AZ3146, NMS-P715, and CCT251455, identifying five point mutations in the kinase domain of MPS1 that confer resistance against multiple inhibitors. Structural studies showed how the MPS1 mutants conferred resistance by causing steric hindrance to inhibitor binding. Notably, we show that these mutations occur in nontreated cancer cell lines and primary tumor specimens, and that they also preexist in normal lymphoblast and breast tissues. In a parallel piece of work, we also show that the EGFR p.T790M mutation, the most common mutation conferring resistance to the EGFR inhibitor gefitinib, also preexists in cancer cells and normal tissue. Our results therefore suggest that mutations conferring resistance to targeted therapy occur naturally in normal and malignant cells and these mutations do not arise as a result of the increased mutagenic plasticity of cancer cells.

Naturally Occurring Mutations in the MPS1 Gene Predispose Cells to Kinase Inhibitor Drug Resistance.,Gurden MD, Westwood IM, Faisal A, Naud S, Cheung KM, McAndrew C, Wood A, Schmitt J, Boxall K, Mak G, Workman P, Burke R, Hoelder S, Blagg J, Van Montfort RL, Linardopoulos S Cancer Res. 2015 Aug 15;75(16):3340-54. doi: 10.1158/0008-5472.CAN-14-3272. Epub , 2015 Jul 22. PMID:26202014<ref>PMID:26202014</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5ap3" style="background-color:#fffaf0;"></div>

==See Also==
*[[Dual specificity protein kinase 3D structures|Dual specificity protein kinase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Dual-specificity kinase]]
[[Category: Human]]
[[Category: Large Structures]]
[[Category: Blagg, J]]
[[Category: Boxall, K]]
[[Category: Burke, R]]
[[Category: Cheung, K J]]
[[Category: Faisal, A]]
[[Category: Gurden, M D]]
[[Category: Hoelder, S]]
[[Category: Linardopoulos, S]]
[[Category: Mak, G]]
[[Category: McAndrew, C]]
[[Category: Montfort, R L.M van]]
[[Category: Naud, S]]
[[Category: Schmitt, J]]
[[Category: Westwood, I M]]
[[Category: Wood, A]]
[[Category: Workman, P]]
[[Category: Drug resistance]]
[[Category: Mitosis]]
[[Category: Mps1]]
[[Category: Protein kinase]]
[[Category: Transferase]]