PDBsum entry 2zmd

Transferase

PDB id: 2zmd

Contents

Protein chain

259 a.a. *

Ligands

537

7PE

Waters ×26

* Residue conservation analysis

PDB id:

2zmd

Name:

Transferase

Title:

Crystal structure of human mps1 catalytic domain t686a mutant in complex with sp600125 inhibitor

Structure:

Dual specificity protein kinase ttk. Chain: a. Fragment: unp residues 510-857, catalytic domain. Synonym: monopolar spindle 1, phosphotyrosine picked threonine- protein kinase, pyt. Engineered: yes. Mutation: yes

Source:

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

Resolution:

2.88Å R-factor: 0.223 R-free: 0.261

Authors:

M.L.H.Chu,L.M.G.Chavas,K.T.Douglas,P.A.Eyers,L.Tabernero

Key ref:

M.L.Chu et al. (2008). Crystal Structure of the Catalytic Domain of the Mitotic Checkpoint Kinase Mps1 in Complex with SP600125. J Biol Chem, 283, 21495-21500. PubMed id: 18480048 DOI: 10.1074/jbc.M803026200

Date:

16-Apr-08 Release date: 13-May-08

Protein chain

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

Seq: 857 a.a.

Struc: 259 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

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: 10.1074/jbc.M803026200

J Biol Chem 283:21495-21500 (2008)

PubMed id: 18480048

Crystal Structure of the Catalytic Domain of the Mitotic Checkpoint Kinase Mps1 in Complex with SP600125.

M.L.Chu, L.M.Chavas, K.T.Douglas, P.A.Eyers, L.Tabernero.

ABSTRACT

Chromosomal instability can result from defective control of checkpoints and is associated with malignant cell growth. Monopolar spindle 1 (Mps1) is a dual-specificity protein kinase that has important roles in the prevention of aneuploidy during the cell cycle and might therefore be a potential target for new therapeutic agents in the treatment of cancer. To gain insights into the molecular mechanism of Mps1 inhibition by small molecules, we determined the x-ray structure of Mps1, both alone and in complex with the ATP-competitive inhibitor SP600125. Mps1 adopts a classic protein kinase fold, with the inhibitor sitting in the ATP-binding site where it is stabilized by hydrophobic interactions. We identified a secondary pocket, not utilized by SP600125, which might be exploited for the rational design of specific Mps1 inhibitors. These structures provide important insights into the interaction of this protein kinase with small molecules and suggest potential mechanisms for Mps1 regulation.

Selected figure(s)

Figure 2.
FIGURE 2. Overall structure of human Mps1 catalytic domain. A, ribbon representation of the structure of Mps1 kinase domain. Characteristic key features important for substrate binding and catalysis are labeled as follows: glycine loop (orange), C helix, catalytic loop (cyan), and activation loop with DFG motif (blue) and p + 1 loop (purple). B, comparison of Mps1 apo-WT (green) and T686A (brown) with phosphorylated Aurora A (P-ArA, red, PDB ID 1OL5) and unphosphorylated Aurora A (unP-ArA, gray, PDB ID 1MUO). Displacement of helix C, due to the conformation of the activation loop in the unphosphorylated structures, results in a shift of the glutamic acid residue and loss of interaction with the catalytically important lysine. C, superposition of the p + 1 loop between WT apo-kinase (green) and T686A-SP600125 complex (gold). The positions of Thr-686 and Ala-686 are indicated.

Figure 3.
FIGURE 3. Structural insights of the SP600125-binding site. A, detailed view of the structure of T686A-SP600125 complex, showing SP600125 bound in the ATP-binding site. The residues that interact with SP600125 are depicted as sticks. The 2F[o] - F[c] map around SP600125 is shown, contoured at 1.5 . B, surface representation (stereo view) of the inhibitor-binding site in Mps1 and JNK1 (PDB ID 1UKI [PDB] ) with SP600125 shown in yellow. Important differences in the composition and orientation of key residues (Mps1^Lys-553/JNK1^Lys-55, Mps1^Cys-604/JNK1^Leu-110, Mps1^Tyr-591/JNK1^Ile-106, Mps1^Tyr-568, Mps1^Glu-571, JNK1^Glu-73, JNK1^Met-77, Mps1^Met-602/JNK1^Met-108, and Mps1^Ile-663/JNK1^Leu-168) can be exploited for the rational design of Mps1-specific inhibitors. C, surface representation of the SP600125-binding site in human Mps1. A molecule of PEG from the crystallization solution is bound in a secondary pocket next to the catalytic Lys-553.

The above figures are reprinted by permission from the ASBMB: J Biol Chem (2008, 283, 21495-21500) copyright 2008.

Figures were selected by an automated process.