5NTT

Crystal structure of human Mps1 (TTK) C604Y mutant in complex with NMS-P715

5NTT の概要

• エントリーDOI: 10.2210/pdb5ntt/pdb
• 分子名称: Dual specificity protein kinase TTK, N-(2,6-DIETHYLPHENYL)-1-METHYL-8-({4-[(1-METHYLPIPERIDIN-4-YL)CARBAMOYL]-2-(TRIFLUOROMETHOXY)PHENYL}AMINO)-4,5-DIHYDRO-1H-PYRAZOLO[4,3-H]QUINAZOLINE-3-CARBOXAMIDE, 1,2-ETHANEDIOL, ... (4 entities in total)
• 機能のキーワード: mps1, ttk, kinase, inhibitor, nms-p715, mutant, c604y, transferase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 34189.04

構造登録者

Hiruma, Y.,Joosten, R.P.,Perrakis, A. (登録日: 2017-04-28, 公開日: 2017-07-26, 最終更新日: 2024-01-17)

主引用文献

Hiruma, Y.,Koch, A.,Hazraty, N.,Tsakou, F.,Medema, R.H.,Joosten, R.P.,Perrakis, A.
Understanding inhibitor resistance in Mps1 kinase through novel biophysical assays and structures.
J. Biol. Chem., 292:14496-14504, 2017

PubMed Abstract: Monopolar spindle 1 (Mps1/TTK) is a protein kinase essential in mitotic checkpoint signaling, preventing anaphase until all chromosomes are properly attached to spindle microtubules. Mps1 has emerged as a potential target for cancer therapy, and a variety of compounds have been developed to inhibit its kinase activity. Mutations in the catalytic domain of Mps1 that give rise to inhibitor resistance, but retain catalytic activity and do not display cross-resistance to other Mps1 inhibitors, have been described. Here we characterize the interactions of two such mutants, Mps1 C604Y and C604W, which raise resistance to two closely related compounds, NMS-P715 and its derivative Cpd-5, but not to the well characterized Mps1 inhibitor, reversine. We show that estimates of the IC (employing a novel specific and efficient assay that utilizes a fluorescently labeled substrate) and the binding affinity ( ) indicate that, in both mutants, Cpd-5 should be better tolerated than the closely related NMS-P715. To gain further insight, we determined the crystal structure of the Mps1 kinase mutants bound to Cpd-5 and NMS-P715 and compared the binding modes of Cpd-5, NMS-P715, and reversine. The difference in steric hindrance between Tyr/Trp and the trifluoromethoxy moiety of NMS-P715, the methoxy moiety of Cpd-5, and complete absence of such a group in reversine, account for differences we observe Our analysis enforces the notion that inhibitors targeting Mps1 drug-resistant mutations can emerge as a feasible intervention strategy based on existing scaffolds, if the clinical need arises.

PubMed: 28726638
DOI: 10.1074/jbc.M117.783555

実験手法

X-RAY DIFFRACTION (2.75 Å)