| Structural highlights
3hmo is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , , , |
| Related: | 2zmc, 2zmd, 3hmn, 3hmp |
| Gene: | MPS1L1, TTK (HUMAN) |
| Activity: | Dual-specificity kinase, with EC number 2.7.12.1 |
| 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]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
The dual-specificity protein kinase monopolar spindle 1 (Mps1) is a central component of the mitotic spindle assembly checkpoint (SAC), a sensing mechanism that prevents anaphase until all chromosomes are bioriented on the metaphase plate. Partial depletion of Mps1 protein levels sensitizes transformed, but not untransformed, human cells to therapeutic doses of the anticancer agent Taxol, making it an attractive novel therapeutic cancer target. We have previously determined the X-ray structure of the catalytic domain of human Mps1 in complex with the anthrapyrazolone kinase inhibitor SP600125. In order to validate distinct inhibitors that target this enzyme and improve our understanding of nucleotide binding site architecture, we now report a biophysical and structural evaluation of the Mps1 catalytic domain in the presence of ATP and the aspecific model kinase inhibitor staurosporine. Collective in silico, enzymatic, and fluorescent screens also identified several new lead quinazoline Mps1 inhibitors, including a low-affinity compound termed Compound 4 (Cpd 4), whose interaction with the Mps1 kinase domain was further characterized by X-ray crystallography. A novel biophysical analysis demonstrated that the intrinsic fluorescence of SP600125 changed markedly upon Mps1 binding, allowing spectrophotometric displacement analysis and determination of dissociation constants for ATP-competitive Mps1 inhibitors. By illuminating the structure of the Mps1 ATP-binding site our results provide novel biophysical insights into Mps1-ligand interactions that will be useful for the development of specific Mps1 inhibitors, including those employing a therapeutically validated quinazoline template.
Biophysical and X-ray crystallographic analysis of Mps1 kinase inhibitor complexes.,Chu ML, Lang Z, Chavas LM, Neres J, Fedorova OS, Tabernero L, Cherry M, Williams DH, Douglas KT, Eyers PA Biochemistry. 2010 Mar 2;49(8):1689-701. PMID:20099905[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ 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
- ↑ Chu ML, Lang Z, Chavas LM, Neres J, Fedorova OS, Tabernero L, Cherry M, Williams DH, Douglas KT, Eyers PA. Biophysical and X-ray crystallographic analysis of Mps1 kinase inhibitor complexes. Biochemistry. 2010 Mar 2;49(8):1689-701. PMID:20099905 doi:10.1021/bi901970c
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