5LJJ

Crystal structure of human Mps1 (TTK) in complex with Reversine

5LJJ の概要

• エントリーDOI: 10.2210/pdb5ljj/pdb
• 分子名称: Dual specificity protein kinase TTK, N~6~-cyclohexyl-N~2~-(4-morpholin-4-ylphenyl)-9H-purine-2,6-diamine, 1,2-ETHANEDIOL (3 entities in total)
• 機能のキーワード: mps1, reversine, ttk, kinase, mitosis checkpoint, 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: 36630.84

構造登録者

Hiruma, Y.,Joosten, R.P.,Perrakis, A. (登録日: 2016-07-18, 公開日: 2016-10-12, 最終更新日: 2024-01-31)

主引用文献

Hiruma, Y.,Koch, A.,Dharadhar, S.,Joosten, R.P.,Perrakis, A.
Structural basis of reversine selectivity in inhibiting Mps1 more potently than aurora B kinase.
Proteins, 84:1761-1766, 2016

PubMed Abstract: Monopolar spindle 1 (Mps1, also known as TTK) is a protein kinase crucial for ensuring that cell division progresses to anaphase only after all chromosomes are connected to spindle microtubules. Incomplete chromosomal attachment leads to abnormal chromosome counts in the daughter cells (aneuploidy), a condition common in many solid cancers. Therefore Mps1 is an established target in cancer therapy. Mps1 kinase inhibitors include reversine (2-(4-morpholinoanilino)-6-cyclohexylaminopurine), a promiscuous compound first recognized as an inhibitor of the Aurora B mitotic kinase. Here, we present the 3.0-Å resolution crystal structure of the Mps1 kinase domain bound to reversine. Structural comparison of reversine bound to Mps1 and Aurora B, indicates a similar binding pose for the purine moiety of reversine making three conserved hydrogen bonds to the protein main chain, explaining the observed promiscuity of this inhibitor. The cyclohexyl and morpholinoaniline moieties of reversine however, have more extensive contacts with the protein in Mps1 than in Aurora B. This is reflected both in structure-based docking energy calculations, and in new experimental data we present here, that both confirm that the affinity of reversine towards Mps1 is about two orders of magnitude higher than towards Aurora B. Thus, our data provides detailed structural understanding of the existing literature that argues reversine inhibits Mps1 more efficiently than Aurora B based on biochemical and in-cell assays. Proteins 2016; 84:1761-1766. © 2016 Wiley Periodicals, Inc.

PubMed: 27699881
DOI: 10.1002/prot.25174

実験手法

X-RAY DIFFRACTION (3 Å)