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7lqd
From Proteopedia
(Difference between revisions)
(New page: '''Unreleased structure''' The entry 7lqd is ON HOLD Authors: Santiago, A.S., dos Reis, C.V., Serafim, R.A.M., Massirer, K.B., Arruda, P., Edwards, A.M., Counago, R.M., Structural Genom...) |
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| - | '''Unreleased structure''' | ||
| - | + | ==Structure of Human MPS1 (TTK) covalently bound to RMS-07 inhibitor== | |
| + | <StructureSection load='7lqd' size='340' side='right'caption='[[7lqd]], [[Resolution|resolution]] 1.95Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[7lqd]] 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=7LQD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7LQD 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]] 1.95Å</td></tr> | ||
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=TOE:2-[2-(2-METHOXY-ETHOXY)-ETHOXY]-ETHOXYL'>TOE</scene>, <scene name='pdbligand=YB4:~{N}-(2,6-diethylphenyl)-2-[[4-(4-methylpiperazin-1-yl)-2-(propanoylamino)phenyl]amino]-5,6-dihydropyrimido[4,5-e]indolizine-7-carboxamide'>YB4</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=7lqd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7lqd OCA], [https://pdbe.org/7lqd PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7lqd RCSB], [https://www.ebi.ac.uk/pdbsum/7lqd PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7lqd 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 == | ||
| + | Monopolar spindle kinase 1 (MPS1/TTK) is a key element of the mitotic checkpoint and clinically evaluated as a target in the treatment of aggressive tumors such as triple-negative breast cancer. While long drug-target residence times have been suggested to be beneficial in the context of therapeutic MPS1 inhibition, no irreversible inhibitors have been reported. Here we present the design and characterization of the first irreversible covalent MPS1 inhibitor, RMS-07, targeting a poorly conserved cysteine in the kinase's hinge region. RMS-07 shows potent MPS1 inhibitory activity and selectivity against all protein kinases with an equivalent cysteine but also in a broader kinase panel. We demonstrate potent cellular target engagement and pronounced activity against various cancer cell lines. The covalent binding mode was validated by mass spectrometry and an X-ray crystal structure. This proof of MPS1 covalent ligandability may open new avenues for the design of MPS1-specific chemical probes or drugs. | ||
| - | + | Development of the First Covalent Monopolar Spindle Kinase 1 (MPS1/TTK) Inhibitor.,M Serafim RA, da Silva Santiago A, Schwalm MP, Hu Z, Dos Reis CV, Takarada JE, Mezzomo P, Massirer KB, Kudolo M, Gerstenecker S, Chaikuad A, Zender L, Knapp S, Laufer S, Counago RM, Gehringer M J Med Chem. 2022 Feb 15. doi: 10.1021/acs.jmedchem.1c01165. PMID:35167750<ref>PMID:35167750</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| - | [[Category: | + | <div class="pdbe-citations 7lqd" style="background-color:#fffaf0;"></div> |
| - | [[Category: | + | == References == |
| - | [[Category: | + | <references/> |
| - | [[Category: Edwards | + | __TOC__ |
| - | [[Category: | + | </StructureSection> |
| - | [[Category: | + | [[Category: Homo sapiens]] |
| - | [[Category: | + | [[Category: Large Structures]] |
| - | [[Category: | + | [[Category: Arruda P]] |
| + | [[Category: Counago RM]] | ||
| + | [[Category: Edwards AM]] | ||
| + | [[Category: Massirer KB]] | ||
| + | [[Category: Santiago AS]] | ||
| + | [[Category: Serafim RAM]] | ||
| + | [[Category: Dos Reis CV]] | ||
Current revision
Structure of Human MPS1 (TTK) covalently bound to RMS-07 inhibitor
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