PDBsum entry 3wyx

Transferase

PDB id: 3wyx

Contents

Protein chain

258 a.a.

Ligands

O38

Metals

IOD

Waters ×5

PDB id:

3wyx

Name:

Transferase

Title:

Crystal structure of human mps1 catalytic domain in complex with 6- ((3-(cyanomethoxy)-4-(1-methyl-1h-pyrazol-4-yl)phenyl)amino)-2- (cyclohexylamino)nicotinonitrile

Structure:

Dual specificity protein kinase ttk. Chain: a. Fragment: mps1 (ttk) kinase, unp residues 516-820. Synonym: phosphotyrosine picked threonine-protein kinase, pyt. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: ttk, mps1, mps1l1. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

2.90Å R-factor: 0.234 R-free: 0.273

Authors:

K.Kusakabe,N.Ide,Y.Daigo,T.Itoh,T.Yamamoto,E.Kojima,Y.Mitsuoka, G.Tadano,S.Tagashira,K.Higashino,Y.Okano,Y.Sato,M.Inoue,M.Iguchi, T.Kanazawa,Y.Ishioka,K.Dohi,Y.Kido,S.Sakamoto,S.Ando,M.Maeda, M.Higaki,H.Yoshizawa,H.Mura,Y.Nakamura

Key ref:

K.Kusakabe et al. (2015). A unique hinge binder of extremely selective aminopyridine-based Mps1 (TTK) kinase inhibitors with cellular activity. Bioorg Med Chem Lett, 23, 2247-2260. PubMed id: 25801152 DOI: 10.1016/j.bmc.2015.02.042

Date:

09-Sep-14 Release date: 08-Apr-15

Protein chain

P33981  (TTK_HUMAN) -  Dual specificity protein kinase TTK from Homo sapiens

Seq: 857 a.a.

Struc: 258 a.a.

Enzyme reactions

• Enzyme class: E.C.2.7.12.1 - dual-specificity kinase.
• Reaction:
  1. L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H⁺
  2. L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H⁺
  3. L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1016/j.bmc.2015.02.042

Bioorg Med Chem Lett 23:2247-2260 (2015)

PubMed id: 25801152

A unique hinge binder of extremely selective aminopyridine-based Mps1 (TTK) kinase inhibitors with cellular activity.

K.Kusakabe, N.Ide, Y.Daigo, T.Itoh, T.Yamamoto, E.Kojima, Y.Mitsuoka, G.Tadano, S.Tagashira, K.Higashino, Y.Okano, Y.Sato, M.Inoue, M.Iguchi, T.Kanazawa, Y.Ishioka, K.Dohi, Y.Kido, S.Sakamoto, S.Ando, M.Maeda, M.Higaki, H.Yoshizawa, H.Murai, Y.Nakamura.

ABSTRACT

Mps1, also known as TTK, is a dual-specificity kinase that regulates the spindle assembly check point. Increased expression levels of Mps1 are observed in cancer cells, and the expression levels correlate well with tumor grade. Such evidence points to selective inhibition of Mps1 as an attractive strategy for cancer therapeutics. Starting from an aminopyridine-based lead 3a that binds to a flipped-peptide conformation at the hinge region in Mps1, elaboration of the aminopyridine scaffold at the 2- and 6-positions led to the discovery of 19c that exhibited no significant inhibition for 287 kinases as well as improved cellular Mps1 and antiproliferative activities in A549 lung carcinoma cells (cellular Mps1 IC50=5.3nM, A549 IC50=26nM). A clear correlation between cellular Mps1 and antiproliferative IC50 values indicated that the antiproliferative activity observed in A549 cells would be responsible for the cellular inhibition of Mps1. The X-ray structure of 19c in complex with Mps1 revealed that this compound retains the ability to bind to the peptide flip conformation. Finally, comparative analysis of the X-ray structures of 19c, a deamino analogue 33, and a known Mps1 inhibitor bound to Mps1 provided insights into the unique binding mode at the hinge region.